Amino acid conjugates providing for sustained systemic concentrations of GABA analogues

ABSTRACT

This invention is directed to compounds that provide for sustained systemic concentrations of GABA analogs following administration to animals. This invention is also directed to pharmaceutical compositions including and methods using such compounds.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention is directed to compounds that provide forsustained systemic concentrations of GABA analogs followingadministration to animals. This invention is also directed topharmaceutical compositions including and methods using such compounds.

[0003] 2. State of the Art

[0004] Rapid clearance of drugs from the systemic circulation representsa major impediment to effective clinical use of therapeutic and/orprophylactic compounds. Although multiple factors can influence thesystemic concentrations of drugs achieved following-administration(including drug solubility, dissolution rate, first-pass metabolism,p-glycoprotein and related efflux mechanisms, hepatic/renal elimination,etc), rapid systemic clearance is a particularly significant reason forsuboptimal systemic exposure to many compounds. Rapid systemic clearancemay require that large doses of drug be administered to achieve atherapeutic or prophylactic effect. Such larger doses of the drug,however, may result in greater variability in drug exposure, morefrequent occurrence of side effects, or decrease in patient compliance.Frequent drug administration may also be required to maintain systemicdrug levels above a minimum effective concentration. This problem isparticularly significant for drugs that must be maintained in awell-defined concentration window to provide continuous therapeutic orprophylactic benefit while minimizing adverse effects (including forexample, antibacterial agents, antiviral agents, anticancer agents,anticonvulsants, anticoagulants, etc.).

[0005] Conventional approaches to extend the systemic exposure of drugswith rapid clearance involve the use of formulation or device approachesthat provide a slow or sustained release of drug within the intestinallumen. These approaches are well known in the art and normally requirethat the drug be well absorbed from the large intestine, where suchformulations are most likely to reside while releasing the drug. Drugsthat are amenable to conventional sustained release approaches must beorally absorbed from the intestine and typically traverse thisepithelial barrier by passive diffusion across the apical andbasolateral membranes of the intestinal epithelial cells. Thephysicochemical features of a molecule that favor its passive uptakefrom the intestinal lumen into the systemic circulation include lowmolecular weight (e.g. <500 Da), adequate solubility, and a balance ofhydrophobic and hydrophilic character (logP generally 1.5-4.0) (Naviaand Chaturvedi, P. R. Drug Discovery Today 1996, 1, 179-189).

[0006] Polar or hydrophilic compounds are typically poorly absorbedthrough an animal's intestine as there is a substantial energeticpenalty for passage of such compounds across the lipid bilayers thatconstitute cellular membranes. Many nutrients that result from thedigestion of ingested foodstuffs in animals, such as amino acids, di-and tripeptides, monosaccharides, nucleosides and water-solublevitamins, are polar compounds whose uptake is essential to the viabilityof the animal. For these substances there exist specific mechanisms foractive transport of the solute molecules across the apical membrane ofthe intestinal epithelia. This transport is frequently energized byco-transport of ions down a concentration gradient. Solute transporterproteins are generally single sub-unit, multi-transmembrane spanningpolypeptides, and upon binding of their substrates are believed toundergo conformational changes, which result in movement of thesubstrate(s) across the membrane.

[0007] Over the past 10-15 years, it has been found that a number oforally administered drugs are recognized as substrates by some of thesetransporter proteins, and that this active transport may largely accountfor the oral absorption of these molecules (Tsuji and Tamai, Pharm. Res.1996, 13, 963-977). While in most instances the transporter substrateproperties of these drugs were unanticipated discoveries made throughretrospective analysis, it has been appreciated that, in principle, onemight achieve good intestinal permeability for a drug by designing inrecognition and uptake by a nutrient transport system. Drugs subject toactive absorption in the small intestine are often unable to passivelydiffuse across epithelial cell membranes and are too large to passthrough the tight junctions that exist between the intestinal cells.These drugs include many compounds structurally related to amino acids,dipeptides, sugars, nucleosides, etc. (for example, many cephalosporins,ACE inhibitors, AZT, etc).

[0008] Gamma (“y”)-aminobutyric acid (“GABA”) is one of the majorinhibitory transmitters in the central nervous system of mammals. GABAis not transported efficiently into the brain from the bloodstream(i.e., GABA does not effectively cross the blood-brain barrier).Consequently, brain cells provide virtually all of the GABA found in thebrain (GABA is biosynthesized by decarboxylation of glutamic acid withpyridoxal phosphate).

[0009] GABA regulates neuronal excitability through binding to specificmembrane proteins (i.e., GABAA receptors), which results in opening ofan ion channel. The entry of chloride ion through the ion channel leadsto hyperpolarization of the recipient cell, which consequently preventstransmission of nerve impulses to other cells. Low levels of GABA havebeen observed in individuals suffering from epileptic seizures, motiondisorders (e.g., multiple sclerosis, action tremors, tardivedyskinesia), panic, anxiety, depression, alcoholism and manic behavior.

[0010] The implication of low GABA levels in a number of common diseasestates and/or common medical disorders has stimulated intensive interestin preparing GABA analogs, which have superior pharmaceutical propertiesin comparison to GABA (e.g., the ability to cross the blood brainbarrier). Accordingly, a number of GABA analogs, with considerablepharmaceutical activity have been synthesized in the art (See, e.g.,Satzinger et al., U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat.No. 5,563,175; Horwell et al., U.S. Pat. No. 6,020,370; Silverman etal., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932;Silverman et al., U.S. Pat. No. 6,117,906; Silverman, InternationalApplication No. WO 92/09560; Silverman et al., International ApplicationNo. WO 93/23383; Horwell et al., International Application No. WO97/29101, Horwell et al., International Application No. WO 97/33858;Horwell et al., International Application No. WO 97/33859; Bryans etal., International Application No. WO 98/17627; Guglietta et al.,International Application No. WO 99/08671; Bryans et al., InternationalApplication No. WO 99/21824; Bryans et al., International ApplicationNo. WO 99/31057; Belliotti et al., International Application No. WO99/31074; Bryans et al., International Application No. WO 99/31075;Bryans et al., International Application No. WO 99/61424; Bryans et al.,International Application No. WO 00/15611; Bryans, InternationalApplication No. WO 00/31020; Bryans et al., International ApplicationNo. WO 00/50027; and Bryans et al, International Application No. WO02/00209).

[0011] Pharmaceutically important GABA analogs include, for example,gabapentin, pregabalin, vigabatrin and baclofen. Gabapentin is alipophilic GABA analog that can pass through the blood-brain barrier,which has been used to clinically treat epilepsy since 1994. Gabapentinalso has potentially useful therapeutic effects in chronic pain states(e.g., neuropathic pain, muscular and skeletal pain), psychiatricdisorders (e.g., panic, anxiety, depression, alcoholism and manicbehavior), movement disorders (e.g., multiple sclerosis, action tremors,tardive dyskinesia), etc. (Magnus, Epilepsia, 1999, 40:S66-S72).Currently, gabapentin is also used in the clinical management ofneuropathic pain. Pregabalin, which possesses greater potency inpre-clinical models of pain and epilepsy than gabapentin is presently inPhase III clinical trials.

[0012] Rapid systemic clearance is a significant problem with many GABAanalogs including gabapentin, which consequently require frequent dosingto maintain a therapeutic or prophylactic concentration in the systemiccirculation (Bryans et al., Med. Res. Rev., 1999, 19, 149-177). Forexample, dosing regimens of 300-600 mg doses of gabapentin administeredthree times per day are typically used for anticonvulsive therapy.Higher doses (1800-3600 mg/day in divided doses) are typically used forthe treatment of neuropathic pain states.

[0013] Sustained released formulations are a conventional solution tothe problem of rapid systemic clearance, as is well known to those ofskill in the art (See, e.g., “Remington's Pharmaceutical Sciences,”Philadelphia College of Pharmacy and Science, 17th Edition, 1985).Osmotic delivery systems are also recognized methods for sustained drugdelivery (See, e.g., Verma et al., Drug Dev. Ind. Pharm., 2000,26:695-708). Many GABA analogs, including gabapentin and pregabalin, arenot absorbed via the large intestine. Rather, these compounds aretypically absorbed in the small intestine by the large neutral aminoacid transporter (“LNAA”) (Jezyk et al., Pharm. Res., 1999, 16,519-526). The rapid passage of conventional dosage forms through theproximal absorptive region of the gastrointestinal tract has preventedthe successful application of sustained release oral dosage technologiesto GABA analogs. Thus, there is a significant need for effectivesustained release versions of GABA analogs to minimize increased dosingfrequency due to rapid systemic clearance of these compounds.

[0014] Another deficiency with some GABA analogs, including gabapentin,is their lack of dose-proportional oral bioavailability (see Radulovicet al, Drug Metab. Dispos. 1995, 23, 441-448; Gidal et al, Epilepsy Res.2000, 40, 123-127; Gabapentin Supplementary Basis for Approval,Warner-Lambert, Inc.). Absorption of gabapentin in mammals is subject tosaturation, since the large neutral amino acid transport system haslimited substrate capacity and is localized to the upper part of thesmall intestine, creating an absorption window that restricts theability of the drug to be taken up into the bloodstream. Thus in man,gabapentin oral bioavailability decreases from about 60% at a dose of300 mg to about 35% at a dose of 1600 mg. This leads not only toinefficient use of the administered drug, but also to unpredictable andhighly variable drug levels in patients, particularly at the higherdoses associated with efficacy in the treatment of epilepsy andneuropathic pain (Gidal et al, Epilepsy Res. 1998, 31, 91-99). There is,therefore, a need for derivatives of gabapentin and other GABA analogs,which following oral administration to a patient in need of therapyprovide therapeutically efficacious levels of the GABA analog in theplasma of a patient, where the concentration of the GABA analog inplasma of the patient over time provides a curve of concentration of theGABA analog in the plasma over time, the curve having an area under thecurve (AUC) which is substantially more proportional to the dose of GABAanalog administered, as compared to the proportionality achievedfollowing oral administration of the GABA analog itself. There issimilarly a need for derivatives of gabapentin and other GABA analogs,which following oral administration to a patient in need of therapyprovide therapeutically efficacious levels of the GABA analog in theplasma of a patient, where the concentration of the GABA analog inplasma of the patient over time provides a curve of concentration of theGABA analog in the plasma over time, the curve having a maximum plasmaconcentration (C_(max)) which is substantially more proportional to thedose of GABA analog administered, as compared to the proportionalityachieved following oral administration of the GABA analog itself.

[0015] One pathway that might provide for the sustained delivery ofdrugs with rapid systemic clearance is the proton-coupled peptidetransport system (Leibach and Ganapathy, Ann. Rev. Nutr. 1996, 16,99-119). These transporters mediate the cellular uptake of small intactpeptides consisting of two or three amino acids and are found primarilyin the intestine and kidney. In the intestine, where small peptides arenot well-absorbed by passive diffusion, the transporters act as avehicle for their effective absorption. Transporters in the kidneyactively reabsorb di- and tri-peptides from the glomerular filtrate,thereby increasing their half-life in the circulation.

[0016] Two proton-coupled peptide transporters that have been cloned andcharacterized are PEPT1 and PEPT2. PEPT1 is a low-affinity,high-capacity transporter found primarily in the intestine. The humanPEPT1 consists of 708 amino acids and possesses 12 putativetransmembrane domains. PEPT2, in contrast, is a high-affinity,low-capacity transporter found mostly in the kidney. It consists of 729amino acids and is 50% identical to human intestinal PEPT1.

[0017] Studies of PEPT1 and PEPT2 have shown that the transportersaccount for the absorption and reabsorption of certain therapeuticallyactive compounds. The compounds include both biologically activepeptides (e.g., renin inhibitors) and zwitterionic antibiotics. Based onthese observations, researchers have suggested that peptidetransporters, in conjunction with cytosolic peptidases, could beexploited for systemic delivery of certain drugs in the form of peptideprodrugs (see Tsuji and Tamai, Pharm. Res. 1996, 13, 963-977). Dipeptideanalogues of α-methyldopa, L-α-methyldopa-Phe and L-α-methyldopa-Pro,for example, are absorbed more efficiently in the intestine thanα-methyldopa alone. Once across the intestinal membrane, the dipeptidesare hydrolyzed by cytosolic peptidases to release α-methyldopa.

[0018] Gallop et al have provided evidence from transporter mRNAexpression profiling studies that PEPT expression in rat and humanextends broadly over the length of the intestine, including the colon(U.S. Patent Application Serial No. 60/351,808 filed Jan. 24, 2002).They have suggested that sustained exposure to a substrate for a PEPTtransporter could be achieved by formulating such a compound in anextended-release dosage form, which would gradually release the compoundduring transit of the formulation through the large intestine.

[0019] Peptide prodrug derivatives of gabapentin and other GABA analogdrugs are contemplated by Bryans et al (see International ApplicationNo. WO 01/90052; U.K. Application GB 2,362,646; European Application EP1,178,034). These workers have disclosed gabapentin derivatives whereinthe amino group is blocked with particular α-aminoacyl or dipeptidemoieties. More specifically, the α-amino acids comprising these peptideprodrug derivatives are the 20 naturally encoded α-amino acids, plusphenylglycine.

[0020] Prodrug derivatives of gabapentin and other GABA analog drugs arealso disclosed by Gallop et al (see the co-pending InternationalApplications WO 02/28881, WO 02/28883, WO 02/28411 and WO 02/32376). Thecompounds disclosed therein are bile acid conjugates of GABA analogsthat are designed to be actively transported across the intestinalmucosa via interaction with the ileal bile acid transporter. Theseconjugates are further designed to undergo enterohepatic recirculationand to slowly release the parent GABA analog into the systemiccirculation. Additional prodrug derivatives of gabapentin and other GABAanalog drugs are disclosed by Gallop et al (see the co-pendingInternational Application WO 02/42414). The compounds disclosed thereinare α-aminoacyl and β-aminoacyl conjugates of GABA analogs that aredesigned to be actively absorbed across the intestinal mucosa viainteraction with peptide transporters expressed in the intestine.

SUMMARY OF THE INVENTION

[0021] This invention is directed to the surprising discovery that PEPT1and PEPT2 oligopeptide transporters can be utilized to provide sustainedsystemic concentrations of drugs administered to an animal. Thisinvention, therefore, permits sustained therapeutic or prophylacticsystemic blood concentrations of GABA analogues which heretofore couldnot be achieved. The present invention addresses the deficiencies ofknown GABA analogs by providing prodrugs of GABA analogs, andcompositions of prodrugs of GABA analogs and methods for making prodrugsof GABA analogs. The present invention also provides methods for usingprodrugs of GABA analogs and methods for using compositions of prodrugsof GABA analogs for treating or preventing common diseases and/ordisorders. The prodrugs of the present invention are substrates forpeptide transporters (PEPT1 and/or PEPT2) expressed in the mammaliangastrointestinal tract. This invention also provides sustained releasedosage formulations containing prodrugs of GABA analogs that aresubstrates for peptide transporters, and the use of such formulations tominimize the frequency of dosing necessary to treat patients in need ofGABA analog therapy.

[0022] Accordingly, in one of its aspects, this invention is directed toa compound of Formula (I):

H—I_(i)-J_(j)-D-K_(k)—OH   (I)

[0023] wherein:

[0024] H is hydrogen;

[0025] I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

[0026] J is —[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

[0027] K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

[0028] wherein a, b, c, d, e and f are independently 0 or 1, providedthat at least one of a and b is 1, at least one of c and d is 1, and atleast one of e and f is 1;

[0029] and wherein i, j and k are independently 0 or 1, provided that atleast one of i, j and k is 1;

[0030] D is a moiety derived from a GABA analog having the followingstructure:

[0031] wherein:

[0032] R³ is a covalent bond linking the GABA analog moiety to J_(j);

[0033] R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to whichthey are attached form an azetidine, substituted azetidine, pyrrolidineor substituted pyrrolidine ring;

[0034] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

[0035] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

[0036] R⁹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0037] R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0038] R¹¹ is C(O)R¹², wherein R¹² is a covalent bond linking the GABAanalog moiety to K_(k);

[0039] R⁵⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

[0040] R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0041] R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0042] R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0043] R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0044] R⁵⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl or R⁵⁵ and R⁵⁶, together with the atoms to which they areattached form a heterocyclyl ring;

[0045] R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0046] R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0047] R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0048] R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0049] R⁶⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl or R⁶⁰ and R⁶¹, together with the atoms to which they areattached form a heterocyclyl ring;

[0050] R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0051] R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0052] R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0053] R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0054] and pharmaceutically acceptable salts, hydrates and solvatesthereof,

[0055] provided that if k is 0 then neither I nor J is derived fromalanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine, valine or phenylglycine;

[0056] and provided that when R⁵, R⁶, R⁹ and R¹⁰ are each hydrogen, thenR⁷ and R⁸ are neither both hydrogen nor both methyl;

[0057] and yet further provided that when D is either of the followingmoieties

[0058] neither I nor J are selected from a group of moieties selectedfrom the following moieties: H₂NCH₂C(O)—, H₂NCH(CH₃)C(O)—,NH₂CH₂CH₂C(O)— and

[0059] In a preferred embodiment, the compound of Formula (I) issufficiently stable such that less than 50% of the compound ismetabolized after incubation in vitro with Caco-2 homogenate for 1 hour,as described in more detail in Example 6.

[0060] In another aspect, this invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) and a pharmaceutically acceptable carrier. Thepharmaceutical composition may be used to treat or prevent epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain, muscular pain or skeletal pain), inflammatory disease,insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in apatient.

[0061] In another aspect, this invention is directed to sustainedrelease oral dosage forms comprising a therapeutically effective amountof a compound of Formula (I) and, optionally, a pharmaceuticallyacceptable carrier.

[0062] In another aspect, this invention is directed to a method fortreating or preventing epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, pain (especially neuropathic pain, muscular pain orskeletal pain), inflammatory disease, insomnia, gastrointestinaldisorders or ethanol withdrawal syndrome in a patient. The methodcomprises administering to a patient in need of such therapy atherapeutically effective amount of a compound of Formula (I),optionally with a pharmaceutically acceptable carrier.

[0063] In another aspect, this invention is directed to a method forachieving sustained release of a GABA analog in a patient in need oftherapy. The method comprises orally administering to the patient asustained release dosage form containing a therapeutically effectiveamount of a compound of Formula (I), and optionally, a pharmaceuticallyacceptable carrier.

[0064] In yet another aspect, this invention is directed to a method forachieving improved dose-proportional exposure of a GABA analog in apatient, said method comprising orally administering to the patient atherapeutically effective amount of a compound of Formula (I) and,optionally, a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

[0065]FIG. 1 illustrates the synthesis of aminoacyl and other peptidederivatives of GABA analogs.

[0066]FIG. 2 illustrates the synthesis of L-Aspartyl-Gabapentinderivatives.

[0067]FIG. 3 illustrates the synthesis of L-Tyrosine-Gabapentinderivatives.

DETAILED DESCRIPTION OF THE INVENTION

[0068] This invention is directed to compounds that provide forsustained systemic concentrations of GABA analogues or activemetabolites thereof following administration to animals. This inventionis also directed to methods using the compounds and pharmaceuticalcompositions that are used in such methods. However, prior to describingthis invention in further detail, the following terms will first bedefined:

[0069] Definitions

[0070] As used herein, the term “animal” refers to various species suchas mammalian and avian species including, by way of example, humans,cattle, sheep, horses, dogs, cats, turkeys, chicken, and the like.Preferably, the animal is a mammal and even more preferably is a human.

[0071] “Administering to the animal” refers to delivering a compound ofFormula (I) to an animal through a suitable route. Such routes include,for example, oral, rectal, subcutaneous, intravenous, intramuscular andintranasal. Preferably, the compound is orally administered to theanimal.

[0072] “Orally delivered” and “orally administered” refer to compounds,compositions and/or dosage forms which are administered to an animal inan oral form, preferably, in a pharmaceutically acceptable diluent. Oraldelivery includes ingestion of the compounds, compositions and/or dosageforms, as well as oral gavage of the compounds and compositions.

[0073] “PEPT1 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the intestine. Thistransporter is described and characterized in the literature. See Adibi,S. A., Gastroenterology 1997, 113, 332-340 and Leibach et al., Ann. Rev.Nutr. 1996, 16, 99-119 for a discussion of the transporter.

[0074] “PEPT2 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the kidney. Thistransporter is described and characterized in the literature. See Dieck,S. T. et al., GLIA 1999, 25, 10-20, Leibach et al., Ann. Rev. Nutr.1996, 16, 99-119; and Wong et al., Am. J. Physiol. 1998, 275, C967-C975for a discussion of the transporter.

[0075] “Transported by either a PEPT1 or PEPT2 oligopeptide transporter”refers to the translocation of a molecule across a membrane of a cellexpressing the transporter. The translocation occurs through interactionwith the transporter and is energized by cotransport of H⁺ ions acrossthe membrane.

[0076] “Amino acid” is intended to denote α-amino acids and β-aminoacids only.

[0077] α-Amino acids are molecules of the formula:

HNR⁵⁰—CR⁵¹R⁵²—C(O)OH:

[0078] wherein:

[0079] R⁵⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

[0080] R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0081] R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl.

[0082] β-Amino acids are molecules of formula:

HNR⁵⁰—(CR⁵¹R⁵²)—(CR⁵³R⁵⁴)—C(O)OH:

[0083] wherein:

[0084] R⁵⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

[0085] R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0086] R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0087] R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0088] R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl.

[0089] “Naturally occurring amino acid” refers to any of the alpha-aminoacids that are the chief components of proteins. The amino acids areeither synthesized by living cells or are obtained as essentialcomponents of the diet. Such amino acids include, for example, thefollowing: alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine and valine.

[0090] “Derived from a compound” refers to a moiety that is structurallyrelated to such a compound. The structure of the moiety is identical tothe compound except at 1 or 2 positions. At these positions, either ahydrogen atom attached to a heteroatom or a hydroxyl moiety of acarboxylic acid group has been replaced with a covalent bond that servesas a point of attachment to another moiety. “Derived from an α-aminoacid” is meant to specifically denote that the point of attachment iseither the terminal α-amino group or the terminal α-acid group of theamino acid. For example, the moiety —NHCH₂C(O)— is derived from glycine.In the moiety, both a hydrogen atom on the amino group and a hydroxylportion of the carboxyl group have been replaced with a covalent bond.

[0091] “GABA analog” refers to a compound of the following structure:

[0092] wherein

[0093] R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to whichthey are attached form an azetidine, substituted azetidine, pyrrolidineor substituted pyrrolidine ring;

[0094] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

[0095] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

[0096] R⁹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl; and,

[0097] R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl.

[0098] “Active metabolite of a drug” refers to products of in vivomodification of the drug which have therapeutic or prophylactic effect.

[0099] “Therapeutic or prophylactic blood concentrations” refers tosystemic exposure to a sufficient concentration of a drug or an activemetabolite thereof over a sufficient period of time to effect diseasetherapy or to prevent the onset or reduce the severity of a disease inthe treated animal.

[0100] “Sustained release” refers to release of a drug or an activemetabolite thereof into the systemic circulation over a prolonged periodof time (typically periods of at least six hours) relative to thatachieved by administration of a conventional immediate-releaseformulation of the drug.

[0101] “Conjugating” refers to the formation of a covalent bond.

[0102] “Active transport or active transport mechanism” refers to themovement of molecules across cellular membranes that: a) is directly orindirectly dependent on an energy mediated process (i.e. driven by ATPhydrolysis, ion gradient, etc); or b) occurs by facilitated diffusionmediated by interaction with specific transporter proteins; or c) occursthrough a modulated solute channel.

[0103] “Amino-protecting group” or “amino-blocking group” refers to anygroup which when bound to one or more amino groups prevents reactionsfrom occurring at these amino groups and which protecting groups can beremoved by conventional chemical steps to reestablish the amino group.The particular removable blocking group is not critical and preferredamino blocking groups include, by way of example only, t-butyoxycarbonyl(t-BOC), benzyloxycarbonyl (CBZ), and the like.

[0104] “Carboxyl-protecting group” or “carboxyl-blocking group” refersto any group which when bound to one or more carboxyl groups preventsreactions from occurring at these groups and which protecting groups canbe removed by conventional chemical steps to reestablish the carboxylgroup. The particular removable blocking group is not critical andpreferred carboxyl blocking groups include, by way of example only,esters of the formula —COOR“where R″ is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, substituted aryl, alkaryl, substituted alkaryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic.

[0105] “AUC” is the area under the plasma drug concentration-versus-timecurve extrapolated from zero time to infinity.

[0106] “C_(max)” is the highest drug concentration observed in plasmafollowing an extravascular dose of drug.

[0107] “Prodrug” refers to a derivative of a drug molecule that requiresa transformation within the body to release the active drug. Prodrugsare frequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug. Typically, prodrugs are designed toovercome pharmaceutical and/or pharmacokinetically based problemsassociated with the parent drug molecule that would otherwise limit theclinical usefulness of the drug.

[0108] “Promoiety” refers to a form of protecting group that when usedto mask a functional group within a drug molecule converts the drug intoa prodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.Ideally, the promoiety is rapidly cleared from the body upon cleavagefrom the prodrug.

[0109] “Dose-Proportional Drug Exposure” or “Dose-Proportionality”refers to the situation where either (i) the concentration of a drug inthe plasma of an animal over time (at a therapeutically relevant level)provides a curve of concentration of the drug in the plasma over time,the curve having an area under the curve (AUC) which is substantiallyproportional to the dose of the drug administered; or (ii) theconcentration of a drug in the plasma of an animal over time (at atherapeutically relevant level) provides a curve of concentration of thedrug in the plasma over time, the curve having a maximum plasmaconcentration (C_(max)) which is substantially proportional to the doseof GABA analog administered.

[0110] “Alkyl” refers to alkyl groups preferably having from 1 to 20carbon atoms and more preferably 1 to 6 carbon atoms. This term isexemplified by groups such as methyl, t-butyl, n-heptyl, octyl, dodecyland the like.

[0111] “Substituted alkyl” refers to an alkyl group, preferably of from1 to 20 carbon atoms, having from 1 to 5 substituents selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl,substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substitutedaryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substitutedheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂-NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂-NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkyl/substituted alkyl groups substituted with—SO₂-alkyl, -SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0112] “Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0113] “Substituted alkoxy” refers to the group “substituted alkyl-O—”.

[0114] “Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O), heterocyclic-C(O)—, and substituted heterocyclic-C(O)—wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0115] “Acylamino” refers to the group —C(O)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0116] “Thiocarbonylamino” refers to the group —C(S)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form, together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0117] “Acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O— wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0118] “Alkenyl” refers to alkenyl group preferably having from 2 to 20carbon atoms and more preferably 2 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkenyl unsaturation.

[0119] “Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂-NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, -SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0120] “Alkenyloxy” refers to the group —O-alkenyl.

[0121] “Substituted alkenyloxy” refers to the group —O-substitutedalkenyloxy.

[0122]37 Alkynyl” refers to alkynyl group preferably having from 2 to 20carbon atoms and more preferably 3 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkynyl unsaturation.

[0123] “Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OS02—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR Where R ishydrogen or alkyl.

[0124] “Alkylene” refers to a divalent alkylene group preferably havingfrom 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. Thisterm is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—)and the like.

[0125] “Substituted alkylene” refers to alkylene groups having from 1 to5 substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OS02—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0126] “Alkenylene” refers to a divalent alkenylene group preferablyhaving from 2 to 20 carbon atoms and more preferably 1 to 6 carbon atomsand having from 1 to 2 sites of alkenyl unsaturation. This term isexemplified by groups such as ethenylene (—CH═CH—), propenylene(—CH₂CH═CH—), and the like.

[0127] “Substituted alkenylene” refers to alkenylene groups having from1 to 5 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0128] “Alkynylene” refers to a divalent alkynylene group preferablyhaving from 2 to 20 carbon atoms and more preferably 1 to 6 carbon atomsand having from 1 to 2 sites of alkynyl unsaturation. This term isexemplified by groups such as ethynylene, propynylene and the like.

[0129] “Substituted alkynylene” refers to alkynylene groups having from1 to 5 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0130] “Amidino” refers to the group H₂NC(═NH)— and the term“alkylamidino” refers to compounds having 1 to 3 alkyl groups (e.g.,alkylHNC(═NH)—).

[0131] “Thioamidino” refers to the group RSC(═NH)— where R is hydrogenor alkyl.

[0132] “Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substitutedalkyl, —NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl,—NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl,—NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl,—NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and—NRC(O)substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0133] “Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0134] “Oxycarbonylamino” refers to the groups —OC(O)NH₂, —OC(O)NRR,—OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl,—OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substitutedalkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl,—OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl,—OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and—OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0135] “Oxythiocarbonylamino” refers to the groups —OC(S)NH₂, —OC(S)NRR,—OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl,—OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substitutedalkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl,—OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl,—OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and—OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0136] “Aminocarbonylamino” refers to the groups —NRC(O)NRR,—NRC(O)NR-alkyl, —NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl,—NRC(O)NR-substituted alkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substitutedalkynyl, —NRC(O)NR-aryl, —NRC(O)NR-substituted aryl,—NRC(O)NR-cycloalkyl, —NRC(O)NR-substituted cycloalkyl,—NRC(O)NR-heteroaryl, and —NRC(O)NR-substituted heteroaryl,—NRC(O)NR-heterocyclic, and —NRC(O)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0137] “Aminothiocarbonylamino” refers to the groups —NRC(S)NRR,—NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl,—NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substitutedalkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl,—NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl,—NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl,—NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0138] “Aryl” or “Ar” refers to a monovalent unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)which condensed rings may or may not be aromatic (e.g.,2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7yl, and the like).Preferred aryls include phenyl and naphthyl.

[0139] “Substituted aryl” refers to aryl groups which are substitutedwith from 1 to 3 substituents selected from the group consisting ofhydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino,aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino,aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0140] “Arylene” refers to a divalent unsaturated aromatic carbocyclicgroup of from 6 to 14 carbon atoms having a single ring (e.g.,phenylene) or multiple condensed rings (e.g., naphthylene or anthrylene)which condensed rings may or may not be aromatic. Preferred arylenesinclude phenylene and naphthylene. Substituted arylene refers to arylenegroups which are substituted with from 1 to 3 substituents selected fromthe group consisting of hydroxy, acyl, acylamino, thiocarbonylamino,acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —S02NRR where R is hydrogen or alkyl.

[0141] “Aryloxy” refers to the group aryl-O— which includes, by way ofexample, phenoxy, naphthoxy, and the like.

[0142] “Substituted aryloxy” refers to substituted aryl-O— groups.

[0143] “Aryloxyaryl” refers to the group -aryl-O-aryl.

[0144] “Substituted aryloxyaryl” refers to aryloxyaryl groupssubstituted with from 1 to 3 substituents on either or both aryl ringsselected from the group consisting of hydroxy, acyl, acylamino,thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl,aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0145] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbonatoms having a single cyclic ring including, by way of example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and thelike. This definition also includes bridged groups such as bicyclo[2.2.1]heptane and bicyclo[3.3.1]nonane.

[0146] “Cycloalkyloxy” refers to —O-cycloalkyl.

[0147] “Cycloalkenyl” refers to cyclic alkenyl groups of frm 3 to 10carbon atoms having a single cyclic ring.

[0148] “Cycloalkenyloxy” refers to —O-cycloalkenyl.

[0149] “Substituted cycloalkyl” and “substituted cycloalkenyl” refers toan cycloalkyl or cycloalkenyl group, preferably of from 3 to 10 carbonatoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0150] “Substituted cycloalkyloxy” and “substituted cycloalkenyloxy”refers to —O-substituted cycloalkyl and —O-substituted cycloalkenyloxyrespectively.

[0151] “Cycloalkylene” refers to divalent cyclic alkylene groups of from3 to 10 carbon atoms having a single cyclic ring including, by way ofexample, cyclopropylene, cyclobutylene, cyclopentylene, cyclooctyleneand the like.

[0152] “Cycloalkenylene” refers to a divalent cyclic alkenylene groupsof from 3 to 10 carbon atoms having a single cyclic ring.

[0153] “Substituted cycloalkylene” and “substituted cycloalkenylene”refers to a cycloalkylene or cycloalkenylene group, preferably of from 3to 8 carbon atoms, having from 1 to 5 substituents selected from thegroup consisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy,acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0154] “Cycloalkoxy” refers to —O-cycloalkyl groups.

[0155] “Substituted cycloalkoxy” refers to —O-substituted cycloalkylgroups.

[0156] “Guanidino” refers to the groups —NRC(═NR)NRR, —NRC(═NR)NR-alkyl,—NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl,—NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl,—NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl,—NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl,—NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl,—NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic whereeach R is independently hydrogen and alkyl as well as where one of theamino groups is blocked by conventional blocking groups such as Boc,Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0157] “N,N-Dimethylcarbamyloxy” refers to the group —OC(O)N(CH₃)₂.

[0158] “Guanidinosulfone” refers to the groups —NRC(═NR)NRSO₂-alkyl,—NRC(═NR)NRSO₂-substituted alkyl, —NRC(═NR)NRSO₂-alkenyl,—NRC(═NR)NRSO₂-substituted alkenyl, —NRC(═NR)NRSO₂-alkynyl,—NRC(═NR)NRSO₂-substituted alkynyl, —NRC(═NR)NRSO₂-aryl,—NRC(═NR)NRSO₂-substituted aryl, —NRC(═NR)NRSO₂-cycloalkyl,—NRC(═NR)NRSO₂-substituted cycloalkyl, —NRC(═NR)NRSO₂-heteroaryl, and—NRC(═NR)NRSO₂-substituted heteroaryl, —NRC(═NR)NRSO₂-heterocyclic, and—NRC(═NR)NRSO₂-substituted heterocyclic where each R is independentlyhydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0159] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

[0160] “Heteroaryl” refers to an aromatic carbocyclic group of from 2 to10 carbon atoms and 1 to 4 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur within the ring. Suchheteroaryl groups can have a single ring (e.g., pyridyl or furyl) ormultiple condensed rings (e.g., indolizinyl or benzothienyl). Preferredheteroaryls include pyridyl, pyrrolyl, indolyl and furyl.

[0161] “Substituted heteroaryl” refers to heteroaryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0162] “Heteroarylene” refers to a divalent aromatic carbocyclic groupof from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur within the ring. Suchheteroarylene groups can have a single ring (e.g., pyridylene orfurylene) or multiple condensed rings (e.g., indolizinylene orbenzothienylene). Preferred heteroarylenes include pyridylene,pyrrolylene, indolylene and furylene.

[0163] “Substituted heteroarylene” refers to heteroarylene groups whichare substituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0164] “Heteroaryloxy” refers to the group —O-heteroaryl and“substituted heteroaryloxy” refers to the group —O-substitutedheteroaryl.

[0165] “Heterocycle” or “heterocyclic” refers to a saturated orunsaturated group having a single ring or multiple condensed rings, from1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from thegroup consisting of nitrogen, sulfur or oxygen within the ring wherein,in fused ring systems, one or more the rings can be aryl or heteroaryl.

[0166] “Substituted heterocyclic” refers to heterocycle groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0167] Examples of heterocycles and heteroaryls include, but are notlimited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide,

[0168] 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

[0169] “Heterocyclene” refers to a divalent saturated or unsaturatedgroup having a single ring or multiple condensed rings, from 1 to 10carbon atoms and from 1 to 4 hetero atoms selected from the groupconsisting of nitrogen, sulfur or oxygen within the ring wherein, infused ring systems, one or more the rings can be aryl or heteroaryl.

[0170] “Substituted heterocyclene” refers to heterocyclene groups whichare substituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0171] “Heterocyclyloxy” refers to the group —O-heterocyclic and“substituted heterocyclyloxy” refers to the group —O-substitutedheterocyclic.

[0172] “Thiol” refers to the group —SH.

[0173] “Thioalkyl” refers to the groups —S-alkyl.

[0174] “Substituted thioalkyl” refers to the group —S-substituted alkyl.

[0175] “Thiocycloalkyl” refers to the groups —S-cycloalkyl.

[0176] “Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl.

[0177] “Thioaryl” refers to the group —S-aryl and “substituted thioaryl”refers to the group —S-substituted aryl.

[0178] “Thioheteroaryl” refers to the group —S-heteroaryl and“substituted thioheteroaryl” refers to the group —S-substitutedheteroaryl.

[0179] “Thioheterocyclic” refers to the group —S-heterocyclic and“substituted thioheterocyclic” refers to the group —S-substitutedheterocyclic.

[0180] “Amino” refers to the —NH₂ group.

[0181] “Substituted amino” refers to the —NR′R″ group wherein R′ and R″are independently hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic or where R′ and R″,together with the nitrogen atom pendent thereto, form a heterocyclicring.

[0182] “Pharmaceutically acceptable salt” refers to pharmaceuticallyacceptable salts of a compound of Formula (I), which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like.

[0183] “Pharmaceutically acceptable carrier” refers to a carrier that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes a carrier that is acceptable for veterinary use as well ashuman pharmaceutical use. “A pharmaceutically acceptable carrier” asused in the specification and claims includes both one and more than onesuch carrier.

[0184] “Treating” or “treatment” of a disease includes:

[0185] (1) preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease,

[0186] (2) inhibiting the disease, i.e., arresting or reducing thedevelopment of the disease or its clinical symptoms, or

[0187] (3) relieving the disease, i.e., causing regression of thedisease or its clinical symptoms.

[0188] A “therapeutically effective amount” means the amount of acompound that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

[0189] Utility

[0190] The compounds and methods described herein provide for thesustained release of the GABA analog or active metabolite thereofrelative to dosing with the parent drug itself. For example, a compoundand/or composition of the invention is administered to a patient,preferably a human, suffering from epilepsy, depression, anxiety,psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, pain (especially, neuropathic painand muscular and skeletal pain), inflammatory disease (i.e., arthritis),insomnia, gastrointestinal disorders or ethanol withdrawal syndrome.Further, in certain embodiments, the compounds and/or compositions ofthe invention are administered to a patient, preferably a human, as apreventative measure against various diseases or disorders. Thus, thecompounds and/or compositions of the invention may be administered as apreventative measure to a patient having a predisposition for epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders and ethanolwithdrawal syndrome. Accordingly, the compounds and/or compositions ofthe invention may be used for the prevention of one disease or disorderand concurrently treating another (e.g., prevention of psychosis whiletreating gastrointestinal disorders; prevention of neuropathic painwhile treating ethanol withdrawal syndrome).

[0191] The suitability of the compounds and/or compositions of theinvention in treating epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, pain (especially neuropathic pain and muscular andskeletal pain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders and ethanol withdrawal syndrome may bedetermined by methods described in the art (See, e.g., Satzinger et al.,U.S. Pat. No. 4,024,175; Satzinger et al., U.S. Pat. No. 4,087,544;Woodruff, U.S. Pat. No. 5,084,479; Silverman et al., U.S. Pat. No.5,563,175; Singh, U.S. Pat. No. 6,001,876; Horwell et al., U.S. Pat. No.6,020,370; Silverman et al., U.S. Pat. No. 6,028,214; Horwell et al.,U.S. Pat. No. 6,103,932; Silverman et al., U.S. Pat. No. 6,117,906;Silverman, International Application No. WO 92/09560; Silverman et al.,International Application No. WO 93/23383; Horwell et al., InternationalApplication No. WO 97/29101, Horwell et al, International ApplicationNo. WO 97/33858; Horwell et al., International Application No. WO97/33859; Bryans et al., International Application No. WO 98/17627;Guglietta et al., International Application No. WO 99/08671; Bryans etal., International Application No. WO 99/21824; Bryans et al.,International Application No. WO 99/31057; Magnus-Miller et al.,International Application No. WO 99/37296; Bryans et al., InternationalApplication No. WO 99/31075; Bryans et al., International ApplicationNo. WO 99/61424; Pande, International Application No. WO 00/23067;Bryans, International Application No. WO 00/31020; Bryans et al.,International Application No. WO 00/50027; and Bryans et al,International Application No. WO 02/00209). Procedures for using thecompounds and/or compositions of the invention for treating epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders and ethanolwithdrawal syndrome have also been described in the art (see referencesabove). Thus, it is well with the capability of those of skill in theart to assay and use the compounds and/or of the invention to treatepilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially, neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders and ethanol withdrawal syndrome.

[0192] All of the amino acid linked drugs described herein can also beused as intermediates in order to couple them to bile acids as disclosedpreviously, as in U.S. Provisional Application No. 60/297,472; U.S.Provisional Application No. 60/249,804; and U.S. Provisional ApplicationNo. 60/297,594 (along with the counterpart PCT Applications WO02/28881;WO02/2883; and WO02/32376) show GABA analogs coupled to bile acidsthrough amino acid linkages. U.S. Provisional Application No. 60/297,654(with counterpart PCT Application WO02/28882) shows L-Dopa analogscoupled to bile acids through amino acid linkages. All of theseapplications are incorporated herein by reference in their entirety.

[0193] Preferred Embodiments

[0194] This invention facilitates sustained therapeutic or prophylacticsystemic blood concentrations of GABA analogues which heretofore couldnot be achieved.

[0195] Accordingly, in one of its compound aspects, this invention isdirected to a compound of Formula (I):

H—I_(i)-J_(j)-D-K_(k)—OH (I)

[0196] wherein:

[0197] H is hydrogen;

[0198] I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

[0199] J is —[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

[0200] K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

[0201] wherein a, b, c, d, e and f are independently 0 or 1, providedthat at least one of a and b is 1, at least one of c and d is 1, and atleast one of e and f is 1;

[0202] and wherein i, j and k are independently 0 or 1, provided that atleast one of i, j and k is 1;

[0203] D is a moiety derived from a GABA analog having the followingstructure:

[0204] wherein:

[0205] R³ is a covalent bond linking the GABA analog moiety to J_(j);

[0206] R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to whichthey are attached form an azetidine, substituted azetidine, pyrrolidineor substituted pyrrolidine ring;

[0207] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

[0208] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

[0209] R⁹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0210] R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0211] R¹¹ is C(O)R¹², wherein R¹² is a covalent bond linking the GABAanalog moiety to K_(k);

[0212] R⁵⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

[0213] R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0214] R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0215] R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0216] R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0217] R⁵⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl or R⁵⁵ and R⁵⁶, together with the atoms to which they areattached form a heterocyclyl ring;

[0218] R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0219] R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0220] R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R₅₈ and R⁵⁹ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0221] R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0222] R⁶⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl or R⁶⁰ and R⁶¹, together with the atoms to which they areattached form a heterocyclyl ring;

[0223] R₆₁ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0224] R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0225] R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0226] R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0227] and pharmaceutically acceptable salts, hydrates and solvatesthereof,

[0228] provided that if k is 0 then neither I nor J is derived fromalanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine, valine or phenylglycine;

[0229] and provided that when R⁵, R⁶, R⁹ and R¹⁰ are each hydrogen, thenR⁷ and R⁸ are neither both hydrogen nor both methyl;

[0230] and yet further provided that when D is either of the followingmoieties

[0231] neither I nor J are selected from the group of moietiesconsisting of H₂NCH₂C(O)—, H₂NCH(CH₃)C(O)—, NH₂CH₂CH₂C(O)— and

[0232] Preferably, in a compound of Formula (I), k is 0 and j is 1.

[0233] Preferably, D in a compound of Formula (I) is a moiety selectedfrom a group consisting of the following GABA analog moieties:

[0234] More preferably, D in a compound of Formula (I) is a moietyselected from the group consisting of the following GABA analogmoieties:

[0235] Preferably, in a compound of Formula (I), a and c are 1, and band d are 0.

[0236] Preferably, in a compound of Formula (I), i and k are 0, and j is1.

[0237] Preferably, in a compound of Formula (I), k is 0, and i and j are1.

[0238] Preferably, in a compound of Formula (I), i and j are 0, and k is1.

[0239] Preferably, in a compound of Formula (I), i is 0, and j and k are1.

[0240] Preferably, in a compound of Formula (I), I, J and K are notderived from natural amino acids.

[0241] Preferably, in a compound of Formula (I), at least one of I, Jand K are derived from the group comprising O-phosphoserine andO-phosphotyrosine.

[0242] More preferably, in a compound of Formula (I), i and k are 0, jis 1, c is 1 and d is 0.

[0243] Preferably, in a compound of Formula (I), when i and k are 0, jis 1, c is 1, and d is 0, then R⁵⁵ is hydrogen, R⁵⁷ is hydrogen and R⁵⁶selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl and substitutedheteroaryl. More preferably, R⁵⁶ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substitutedaryl and heteroaryl.

[0244] Preferably, in a compound of Formula (I), when i and k are 0, jis 1, c is 1, d is 0, and R⁵⁷ is hydrogen, then R⁵⁵ and R⁵⁶ togetherwith the atoms to which they are attached form a heterocyclyl orsubstituted heterocyclyl ring. More preferably, R⁵⁵ and R⁵⁶ togetherwith the atoms to which they are attached form an azetidine,4-substituted pyrrolidine, piperidine or substituted piperidine ring.

[0245] Preferably, in a compound of Formula (I), when i and k are 0, jis 1, c is 1, d is 0, and R⁵⁵ is hydrogen, then R⁵⁶ and R⁵⁷ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring. Morepreferably, R⁵⁶ and R⁵⁷ together with the atoms to which they areattached form a cyclopropyl, cyclobutyl, cyclopentyl, substitutedcyclopentyl, cyclohexyl, substituted cyclohexyl, piperidinyl orsubstituted piperidinyl ring.

[0246] In one embodiment of a compound of Formula (I), when i and k are0, j is 1, c is 1, d is 0, R⁵⁵ is hydrogen, R⁵⁷ is hydrogen and R⁵⁶ issubstituted alkyl, then preferably R⁵⁶ is selected from the groupconsisting of arylalkyl, substituted arylalkyl, heteroarylalkyl andsubstituted heteroarylalkyl. More preferably, R⁵⁶ is selected from thegroup consisting of substituted benzyl, s-naphthylmethyl, substituteds-naphthylmethyl, t-pyridylmethyl, substituted t-pyridylmethyl,t-quinolylmethyl, substituted t-quinolylmethyl, u-furanylmethyl,substituted u-furanylmethyl, u-benzofuranylmethyl, substitutedu-benzofuranylmethyl, u-thienylmethyl, substituted u-thienylmethyl,u-benzothienylmethyl, substituted u-benzothienylmethyl,u-pyrrolylmethyl, substituted u-pyrrolylmethyl, substitutedu-indolyhnethyl, u-pyrazinylmethyl, substituted u-pyrazinylmethyl,substituted v-imidazolylmethyl, v-oxazolylmethyl, substitutedv-oxazolylmethyl, v-thiazolylmethyl and substituted v-thiazolylmethyl,wherein s is 1 or 2; t is 2, 3 or 4; u is 2 or 3; and v is 2, 4 or 5.Even more preferably R⁵⁶ is selected from the group consisting of2-methylphenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl,2-methoxyphenylmethyl, 3-methoxyphenylmethyl, 4-methoxyphenylmethyl,2-trifluoromethylphenylmethyl, 3-trifluoromethylphenylmethyl,4-trifluoromethylphenylmethyl, 2-cyanophenylmethyl, 3-cyanophenylmethyl,4-cyanophenylmethyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl,4-fluorophenylmethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl,4-chlorophenylmethyl, 2-bromophenylmethyl, 3-bromophenylmethyl,4-bromophenylmethyl, 2-iodophenylmethyl, 3-iodophenylmethyl,4-iodophenylmethyl, 2,3-difluorophenylmethyl, 2,4-difluorophenylmethyl,2,5-difluorophenylmethyl, 2,6-difluorophenylmethyl,3,4-difluorophenylmethyl, 3,5-difluorophenylmethyl,2,3-dichlorophenylmethyl, 2,4-dichlorophenylmethyl,2,5-dichlorophenylmethyl, 2,6-dichlorophenylmethyl,3,4-dichlorophenylmethyl, 3,5-dichlorophenylmethyl, 1-naphthylmethyl,2-naphthylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-quinolylmethyl, 3-quinolylmethyl, 4-quinolylmethyl, 2-furanylmethyl,3-furanylmethyl, 3-benzofuranylmethyl, 2-thienylmethyl, 3-thienylmethyl,3-benzothienylmethyl, 5-hydroxyindol-3-ylmethyl,5-alkoxyindol-3-ylmethyl, 5-acyloxyindol-3-ylmethyl, 2-oxazolylmethyl,4-oxazolylmethyl 2-thiazolylmethyl and 4-thiazolylmethyl.

[0247] In another embodiment of a compound of Formula (I), when i and kare 0, j is 1, c is 1, d is 0, R⁵⁵ is hydrogen, R⁵⁷ is hydrogen and R⁵⁶is substituted alkyl, then preferably R⁵⁶ is selected from the groupconsisting of —(CH₂)_(n)C(O)XR¹³ and —CH₂[4—C₆H₄—OC(O)R¹⁵],

[0248] wherein:

[0249] n is 1 or 2;

[0250] X is O or NR¹⁴;

[0251] R¹³ and R¹⁴ are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl and substituted heteroaryl, or R¹³ and R¹⁴ together with theatoms to which they are attached form a heterocyclyl or substitutedheterocyclyl ring; and

[0252] R¹⁵ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkoxy, substituted alkoxy, alkenyloxy, substitutedalkenyloxy, alkynyloxy, substituted alkynyloxy, cycloalkoxy, substitutedcycloalkoxy, heterocyclyloxy, substituted heterocyclyloxy, aryloxy,substituted aryloxy, heteroaryloxy and substituted heteroaryloxy;

[0253] with the provisos that when X is O, then R¹³is not hydrogen; andwhen X is NR¹⁴, then R¹³ and R¹⁴ are not both hydrogen.

[0254] Preferred compounds of Formula (I) are compounds selected fromthe group consisting of L-1-Naphthylalanine-Gabapentin,L-2-Naphthylalanine-Gabapentin, L-2-Quinoylalanine-Gabapentin,L-(2-Quinoylalanine N-Oxide)-Gabapentin, L-2-Pyridylalanine-Gabapentin,L-3-Pyridylalanine-Gabapentin, L-(4-Pyridylalanine N-Oxide)-Gabapentin,L-2-Thienylalanine-Gabapentin, L-3-Thienylalanine-Gabapentin,L-3-Benzothienylalanine-Gabapentin, L-4-Thiazolylalanine-Gabapentin,L-2-Methylphenylalanine-Gabapentin, L-4-Methylphenylalanine-Gabapentin,L-2-Trifluoromethylphenylalanine-Gabapentin,L-3-Trifluoromethylphenylalanine-Gabapentin,L-4-Trifluoromethylphenylalanine-Gabapentin,L-2-Fluorophenylalanine-Gabapentin, L-3-Fluorophenylalanine-Gabapentin,L-4-Fluorophenylalanine-Gabapentin, L-2-Chlorophenylalanine-Gabapentin,L-3-Chlorophenylalanine-Gabapentin, L-4-Chlorophenylalanine-Gabapentin,L-4-Bromophenylalanine-Gabapentin, L-4-Iodophenylalanine-Gabapentin,L-2-Methoxyphenylalanine-Gabapentin,L-4-Methoxyphenylalanine-Gabapentin, L-4-Ethoxyphenylalanine-Gabapentin,L-3-Cyanophenylalanine-Gabapentin, L-4-Cyanophenylalanine-Gabapentin,L-3,4-Difluorophenylalanine-Gabapentin,L-3,5-Difluorophenylalanine-Gabapentin, D,L-2,4-Difluorophenylalanine-Gabapentin, D,L-2,6-Difluorophenylalanine-Gabapentin,L-2,4-Dichlorophenylalanine-Gabapentin,L-3,4-Dichlorophenylalanine-Gabapentin, L-Pipecolyl-Gabapentin,L-tert-Butylglycine-Gabapentin, L-2,3-Diaminopropionyl-Gabapentin,L-Norvaline-Gabapentin, L-Penicillamine-Gabapentin,1-Aminocyclopropane-1-Carbonyl-Gabapentin,1-Aminocyclohexane-1-Carbonyl-Gabapentin,L-Homophenylalanine-Gabapentin, L-Aspartyl-β-(Pyrrolidinyl)-Gabapentin,L-Aspartyl-β-(Butylamido)-Gabapentin,L-Aspartyl-β-(2-Methoxyethylamido)-Gabapentin,L-Aspartyl-β-(Piperidinyl)-Gabapentin,L-Aspartyl-β-(3-Methylbutylamido)-Gabapentin,L-Aspartyl-β-(Cyclohexylamido)-Gabapentin,L-Aspartyl-β-(4-Amidomethylpyridine)-Gabapentin,L-Aspartyl-β-(3-Amidomethylpyridine)-Gabapentin,L-Aspartyl-β-(Heptylamido)-Gabapentin,L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Gabapentin,L-Aspartyl-β-(O-Cyclohexyl ester)-Gabapentin, L-Aspartyl-β-(O-Benzylester)-Gabapentin, L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Gabapentin,L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Gabapentin,L-Tyrosine-(O-2-Methylbenzoyl)-Gabapentin,L-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Gabapentin,L-1-Naphthylalanine-Pregabalin, L-2-Naphthylalanine-Pregabalin,L-2-Quinoylalanine-Pregabalin, L-(2-Quinoylalanine N-Oxide)-Pregabalin,L-2-Pyridylalanine-Pregabalin, L-3-Pyridylalanine-Pregabalin,L-(4-Pyridylalanine N-Oxide)-Pregabalin, L-2-Thienylalanine-Pregabalin,L-3-Thienylalanine-Pregabalin, L-3-Benzothienylalanine-Pregabalin,L-4-Thiazolylalanine-Pregabalin, L-2-Methylphenylalanine-Pregabalin,L-4-Methylphenylalanine-Pregabalin,L-2-Trifluoromethylphenylalanine-Pregabalin,L-3-Trifluoromethylphenylalanine-Pregabalin,L-4-Trifluoromethylphenylalanine-Pregabalin,L-2-Fluorophenylalanine-Pregabalin, L-3-Fluorophenylalanine-Pregabalin,L-4-Fluorophenylalanine-Pregabalin, L-2-Chlorophenylalanine-Pregabalin,L-3-Chlorophenylalanine-Pregabalin, L-4-Chlorophenylalanine-Pregabalin,L-4-Bromophenylalanine-Pregabalin, L-4-Iodophenylalanine-Pregabalin,L-2-Methoxyphenylalanine-Pregabalin,L-4-Methoxyphenylalanine-Pregabalin, L-4-Ethoxyphenylalanine-Pregabalin,L-3-Cyanophenylalanine-Pregabalin, L-4-Cyanophenylalanine-Pregabalin,L-3,4-Difluorophenylalanine-Pregabalin,L-3,5-Difluorophenylalanine-Pregabalin, D,L-2,4-Difluorophenylalanine-Pregabalin, D,L-2,6-Difluorophenylalanine-Pregabalin,L-2,4-Dichlorophenylalanine-Pregabalin,L-3,4-Dichlorophenylalanine-Pregabalin, L-Pipecolyl-Pregabalin,L-tert-Butylglycine-Pregabalin, L-2,3-Diaminopropionyl-Pregabalin,L—Norvaline-Pregabalin, L-Penicillamine-Pregabalin,1-Aminocyclopropane-1-Carbonyl-Pregabalin,1-Aminocyclohexane-1-Carbonyl-Pregabalin,L-Homophenylalanine-Pregabalin, L-Aspartyl-β-(Pyrrolidinyl)-Pregabalin,L-Aspartyl-β-(Butylamido)-Pregabalin,L-Aspartyl-β-(2-Methoxyethylamido)-Pregabalin,L-Aspartyl-β-(Piperidinyl)-Pregabalin,L-Aspartyl-β-(3-Methylbutylamido)-Pregabalin,L-Aspartyl-β-(Cyclohexylamido)-Pregabalin,L-Aspartyl-β-(4-Amidomethylpyridine)-Pregabalin,L-Aspartyl-β-(3-Amidomethylpyridine)-Pregabalin,L-Aspartyl-β-(Heptylamido)-Pregabalin,L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Pregabalin,L-Aspartyl-β-(O-Cyclohexyl ester)-Pregabalin, L-Aspartyl-β-(O-Benzylester)-Pregabalin, L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Pregabalin,L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Pregabalin,L-Tyrosine-(O-2-Methylbenzoyl)-Pregabalin andL-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Pregabalin.

[0255] These compounds serve as substrates for the peptide transportersPEPT1 and PEPT2 from both human and rat. Further, in vitro metabolismstudies demonstrate that these compounds function as prodrugs ofgabapentin or pregabalin respectively, undergoing partial or completeconversion to the parent drug after incubation with tissue extracts orisolated enzymes found in gastric fluid or plasma, as described indetail in the Experimental section.

[0256] In a preferred embodiment, the compound of Formula (I) issufficiently stable such that less than 50% of the compound ismetabolized after incubation in vitro with Caco-2 homogenate for 1 hour,as described in more detail in Example 6.

[0257] Preferred compounds of Formula (I) are prodrugs of GABA analogsthat are absorbed from the gastrointestinal tract in mammals byinteraction with intestinal peptide transporters. It is particularlypreferred that these GABA analog prodrugs be sufficiently stable withinthe intestinal lumen to be absorbed intact into the systemiccirculation, but then undergo efficient conversion back to the GABAanalog. This provides a method for achieving better dose-proportionaldrug exposure than can be attained by oral administration of the parentGABA analog itself, since the PEPT transport pathway is less susceptibleto saturation (at high substrate doses) than the large neutral aminoacid transport system typically utilized by GABA analogs.

[0258] In one preferred embodiment, a compound of Formula (I), upon oraladministration to a patient in need of therapy, provides therapeuticallyefficacious levels of the GABA analog in the plasma of the patient,where the concentration of the GABA analog in plasma of the patient overtime provides a curve of concentration of the GABA analog in the plasmaover time, the curve having an area under the curve (AUC) which issubstantially more proportional to the dose of GABA analog administered,as compared to the proportionality achieved following oraladministration of the GABA analog itself. In another preferredembodiment, a compound of Formula (I), upon oral administration to apatient in need of therapy, provides therapeutically efficacious levelsof the GABA analog in the plasma of a patient, where the concentrationof the GABA analog in plasma of the patient over time provides a curveof concentration of the GABA analog in the plasma over time, the curvehaving a maximum plasma concentration (C_(max)β) which is substantiallymore proportional to the dose of GABA analog administered, as comparedto the proportionality achieved following oral administration of theGABA analog itself.

[0259] Prodrugs of GABA analogs that are substrates for the peptidetransporter PEPT1 are candidates for formulation in sustained releaseoral dosage forms. Preferred compounds of Formula (I) are prodrugs ofGABA analogs that are absorbed from the mammalian colon. Followingcolonic administration of these prodrugs, the maximum plasmaconcentrations of the GABA analog, as well as the area under the GABAanalog plasma concentration vs. time curves, are significantly greater(>3-fold) than that produced from colonic administration of the GABAanalog itself.

[0260] Particularly preferred compounds of Formula (I) are compoundsselected from the group consisting of L-2-Thienylalanine-Gabapentin,L-4-Methylphenylalanine-Gabapentin,L-4-Trifluoromethylphenylalanine-Gabapentin,L-2-Fluorophenylalanine-Gabapentin, L-4-Fluorophenylalanine-Gabapentin,L-2-Chlorophenylalanine-Gabapentin, L-4-Chlorophenylalanine-Gabapentin,L-4-Bromophenylalanine-Gabapentin, L-4-Iodophenylalanine-Gabapentin,L-4-Methoxyphenylalanine-Gabapentin, L-4-Ethoxyphenylalanine-Gabapentin,L-4-Cyanophenylalanine-Gabapentin,L-3,4-Difluorophenylalanine-Gabapentin, D,L-2,4-Difluorophenylalanine-Gabapentin, D,L-2,6-Difluorophenylalanine-Gabapentin,L-2,4-Dichlorophenylalanine-Gabapentin andL-3,4-Dichlorophenylalanine-Gabapentin.

[0261] In one aspect, this invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) and a pharmaceutically acceptable carrier. Thepharmaceutical composition may be used to treat or prevent epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain, muscular pain or skeletal pain), inflammatory disease,insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in apatient.

[0262] In another aspect, this invention is directed to sustainedrelease oral dosage forms comprising a therapeutically effective amountof a compound of Formula (I) and, optionally, a pharmaceuticallyacceptable carrier. In one embodiment, the dosage form comprises anosmotic dosage form. In another embodiment, the dosage form comprises aprodrug-releasing polymer. In another embodiment, the dosage formcomprises a prodrug-releasing lipid. In another embodiment, the dosageform comprises a prodrug-releasing wax. In another embodiment, thedosage form comprises tiny timed-release pills. In yet anotherembodiment, the dosage form comprises prodrug releasing beads.Preferably, the prodrug is released from the dosage form over a periodof at least about 6 hours, more preferably at least about 8 hours, andmost preferably at least about 12 hours. Further, the dosage formpreferably releases from 0 to 20% of the prodrug in 0 to 2 hours, from20 to 50% of the prodrug in 2 to 12 hours, from 50 to 85% of the prodrugin 3 to 20 hours and greater than 75% of the prodrug in 5 to 18 hours.

[0263] In another aspect, this invention is directed to a method fortreating or preventing epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, pain (especially neuropathic pain, muscular pain orskeletal pain), inflammatory disease, insomnia, gastrointestinaldisorders or ethanol withdrawal syndrome in a patient. The methodcomprises administering to a patient in need of such therapy atherapeutically effective amount of a compound of Formula (I),optionally with a pharmaceutically acceptable vehicle.

[0264] In another aspect, this invention is directed to a method forachieving sustained release of a GABA analog in a patient in need oftherapy. The method comprises orally administering to the patient asustained release dosage form containing a therapeutically effectiveamount of a compound of Formula (I), and optionally, a pharmaceuticallyacceptable vehicle.

[0265] In yet another aspect, this invention is directed to a method forachieving improved dose-proportional exposure of a GABA analog in apatient, said method comprising orally administering to the patient atherapeutically effective amount of a compound of Formula (I) and,optionally, a pharmaceutically acceptable vehicle.

[0266] Compound Preparation

[0267] Compounds of this invention can be made by various methods,including those illustrated in FIGS. 1-3 and the working examplesprovided below.

[0268] The starting materials and reagents used in preparing thesecompounds are either available from commercial suppliers such as AldrichChemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). These schemes are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

[0269] The starting materials and the intermediates of the reaction maybe isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

[0270] Pharmaceutical Formulations

[0271] When employed as pharmaceuticals, the compounds of Formula (I)are usually administered in the form of pharmaceutical compositions.These compounds can be administered by a variety of routes includingoral, rectal, subcutaneous, intravenous, intramuscular and intranasal.Oral administration of these compounds and compositions is particularlypreferred. Such compositions are prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

[0272] This invention also includes pharmaceutical compositions whichcontain, as the active ingredient, one or more of the compounds ofFormula (I) above associated with pharmaceutically acceptable carriers.In making the compositions of this invention, the active ingredient isusually mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier, which can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

[0273] In preparing a formulation, it may be necessary to mill theactive compound to provide the appropriate particle size prior tocombining with other ingredients. If the active compound issubstantially insoluble, it ordinarily is milled to a particle size ofless than 200 mesh. If the active compound is substantially watersoluble, the particle size is normally adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g. about 40mesh.

[0274] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents. The compositions of the invention can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart.

[0275] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 0.1 to about 5000 mg, more usuallyabout 10 to about 2000 mg, of the active ingredient. The term “unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other animals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

[0276] The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

[0277] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 mg to about 2 g of the activeingredient of the present invention.

[0278] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

[0279] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

[0280] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solventsor mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

[0281] The present compounds and/or compositions of the invention, whichcomprise one or more compounds of the invention, are preferablyadministered orally. In particularly preferred embodiments, thecompounds of the invention may be delivered via sustained releasesystems, preferably oral sustained release systems. Sustained releasedosage forms for oral administration are described in greater detailbelow.

[0282] Sustained Release Oral Dosage Forms of the Invention

[0283] The present invention can be practiced with a number of differentdosage forms, which may be adapted to provide sustained release of theprodrug upon oral administration.

[0284] In one embodiment of the invention, the dosage form comprisesbeads that on dissolution or diffusion release the prodrug over anextended period of hours, preferably, over a period of at least 6 hours,more preferably, over a period of at least 8 hours and most preferably,over a period of at least 12 hours. The prodrug-releasing beads may havea central composition or core comprising a prodrug and pharmaceuticallyacceptable vehicles, including an optional lubricant, antioxidant andbuffer. The beads may be medical preparations with a diameter of about 1to 2 mm. Individual beads may comprise doses of the prodrug, forexample, doses of up to about 40 mg of prodrug. The beads, in oneembodiment, are formed of non-cross-linked materials to enhance theirdischarge from the gastrointestinal tract. The beads may be coated witha release rate-controlling polymer that gives a timed release profile.

[0285] The time release beads may be manufactured into a tablet fortherapeutically effective prodrug administration. The beads can be madeinto matrix tablets by the direct compression of a plurality of beadscoated with, for example, an acrylic resin and blended with excipientssuch as hydroxypropylmethyl cellulose. The manufacture of beads has beendisclosed in the art (Lu, Int. J. Pharm., 1994, 112, 117-124;Pharmaceutical Sciences by Remington, 14th ed, pp1626-1628 (1970);Fincher, J. Pharm. Sci. 1968, 57, 1825-1835 ( ); and U.S. Pat. No.4,083,949) as has the manufacture of tablets (Pharmaceutical Sciences,by Remington, 17th Ed, Ch. 90, pp1603-1625 (1985).

[0286] In another embodiment, an oral sustained release pump may be used(see Langer, supra; Sefton, 1987, CRC Crit Ref Biomed Eng. 14:201;Saudek et al., 1989, N. Engl. J Med. 321:574).

[0287] In another embodiment, polymeric materials can be used (see“Medical Applications of Controlled Release,” Langer and Wise (eds.),CRC Press., Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,”Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, N.Y.(1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem.23:61; see also Levy et al., 1985, Science 228: 190; During et al.,1989, Ann. Neurol. 25:35 1; Howard et al, 1989, J. Neurosurg. 71:105).In a preferred embodiment, polymeric materials are used for oralsustained release delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3)1-9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J.Pharm., 1979, 2, 307).

[0288] In another embodiment, enteric-coated preparations can be usedfor oral sustained release administration. Preferred coating materialsinclude polymers with a pH-dependent solubility (i.e., pH-controlledrelease), polymers with a slow or pH-dependent rate of swelling,dissolution or erosion (i.e., time-controlled release), polymers thatare degraded by enzymes (i.e., enzyme-controlled release) and polymersthat form firm layers that are destroyed by an increase in pressure(i.e., pressure-controlled release).

[0289] In yet another embodiment, drug-releasing lipid matrices can beused for oral sustained release administration. One particularlypreferred example is when solid microparticles of the prodrug are coatedwith a thin controlled release layer of a lipid (e.g., glyceryl behenateand/or glyceryl palmitostearate) as disclosed in Farah et al., U.S. Pat.No. 6,375,987 and Joachim et al., U.S. Pat. No. 6,379,700.. Thelipid-coated particles can optionally be compressed to form a tablet.Another controlled release lipid-based matrix material which is suitablefor sustained release oral administration comprises polyglycolizedglycerides as disclosed in Roussin et al., U.S. Pat. No. 6,171,615.

[0290] In yet another embodiment, prodrug-releasing waxes can be usedfor oral sustained release administration. Examples of suitablesustained prodrug-releasing waxes are disclosed in Cain et al., U.S.Pat. No. 3,402,240 (carnauba wax, candedilla wax, esparto wax andouricury wax); Shtohryn et al. U.S. Pat. No. 4,820,523 (hydrogenatedvegetable oil, bees wax, caranuba wax, paraffin, candelillia, ozokeriteand mixtures thereof); and Walters, U.S. Pat. No. 4,421,736 (mixture ofparaffin and castor wax).

[0291] In still another embodiment, osmotic delivery systems are usedfor oral sustained release administration (Verma et al., Drug Dev. Ind.Pharm., 2000, 26:695-708). In a preferred embodiment, OROSâ systems madeby Alza Corporation, Mountain View, Calif. are used for oral sustainedrelease delivery devices (Theeuwes et al., U.S. Pat. No. 3,845,770;Theeuwes et al., U.S. Pat. No. 3,916,899).

[0292] In yet another embodiment, a controlled-release system can beplaced in proximity of the target of the prodrug of the GABA analog,thus requiring only a fraction of the systemic dose (see, e.g., Goodson,in “Medical Applications of Controlled Release,” supra, vol. 2, pp.115-138 (1984)). Other controlled-release systems discussed in Langer,1990, Science 249:1527-1533 may also be used.

[0293] In another embodiment of the invention, the dosage form comprisesa prodrug of a GABA analog coated on a polymer substrate. The polymercan be an erodible, or a nonerodible polymer. The coated substrate maybe folded onto itself to provide a bilayer polymer drug dosage form. Forexample prodrug of a GABA analog can be coated onto a polymer such as apolypeptide, collagen, gelatin, polyvinyl alcohol, polyorthoester,polyacetyl, or a polyorthocarbonate and the coated polymer folded ontoitself to provide a bilaminated dosage form. In operation, thebioerodible dosage form erodes at a controlled rate to dispense theprodrug over a sustained release period. Representative biodegradablepolymer comprise a member selected from the group consisting ofbiodegradable poly(amides), poly(amino acids), poly(esters), poly(lacticacid), poly(glycolic acid), poly(carbohydrate), poly(orthoester),poly(orthocarbonate), poly(acetyl), poly(anhydrides), biodegradablepoly(dehydropyrans), and poly(dioxinones) which are known in the art(Rosoff, Controlled Release of Drugs, Chap. 2, pp. 53-95 (1989); and inU.S. Pat. Nos. 3,811,444; 3,962,414; 4,066,747, 4,070,347; 4,079,038;and 4,093,709).

[0294] In another embodiment of the invention, the dosage form comprisesa prodrug loaded into a polymer that releases the prodrug by diffusionthrough a polymer, or by flux through pores or by rupture of a polymermatrix. The drug delivery polymeric dosage form comprises aconcentration of 10 mg to 2500 mg homogenously contained in or on apolymer. The dosage form comprises at least one exposed surface at thebeginning of dose delivery. The non-exposed surface, when present, iscoated with a pharmaceutically acceptable material impermeable to thepassage of a prodrug. The dosage form may be manufactured by proceduresknown in the art. An example of providing a dosage form comprisesblending a pharmaceutically acceptable carrier like polyethylene glycol,with a known dose of prodrug at an elevated temperature, like 37° C.,and adding it to a silastic medical grade elastomer with a cross-linkingagent, for example, octanoate, followed by casting in a mold. The stepis repeated for each optional successive layer. The system is allowed toset for 1 hour, to provide the dosage form. Representative polymers formanufacturing the dosage form comprise a member selected from the groupconsisting of olefin, and vinyl polymers, addition polymers,condensation polymers, carbohydrate polymers, and silicon polymers asrepresented by polyethylene, polypropylene, polyvinyl acetate,polymethylacrylate, polyisobutylmethacrylate, poly alginate, polyamideand polysilicon. The polymers and procedures for manufacturing them havebeen described in the art (Coleman et al., Polymers 1990, 31, 1187-1231;Roerdink et al., Drug Carrier Systems 1989, 9, 57-10.; Leong et al.,Adv. Drug Delivery Rev. 1987, 1, 199-233; Roff et al., Handbook ofCommon Polymers 1971, CRC Press; U.S. Pat. No. 3,992,518).

[0295] In another embodiment of the invention, the dosage from comprisesa plurality of tiny pills. The tiny time-released pills provide a numberof individual doses for providing various time doses for achieving asustained-release prodrug delivery profile over an extended period oftime up to 24 hours. The matrix comprises a hydrophilic polymer selectedfrom the group consisting of a polysaccharide, agar, agarose, naturalgum, alkali alginate including sodium alginate, carrageenan, fucoidan,furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gum karaya, grumtragacanth, locust bean gum, pectin, amylopectin, gelatin, and ahydrophilic colloid. The hydrophilic matric comprises a plurality of 4to 50 tiny pills, each tiny pill comprise a dose population of from 10ng, 0.5mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg etc. The tiny pillscomprise a release rate-controlling wall of 0.001 up to 10 mm thicknessto provide for the timed release of prodrug. Representative wall formingmaterials include a triglyceryl ester selected from the group consistingof glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate,glyceryl laureate, glyceryl didecenoate and glyceryl tridenoate. Otherwall forming materials comprise polyvinyl acetate, phthalate,methylcellulose phthalate and microporous olefins. Procedures formanufacturing tiny pills are disclosed in U.S. Pat. Nos. 4,434,153;4,721,613; 4,853,229; 2,996,431; 3,139,383 and 4,752,470.

[0296] In another embodiment of the invention, the dosage form comprisesan osmotic dosage form, which comprises a semipermeable wall thatsurrounds a therapeutic composition comprising the prodrug. In usewithin a patient, the osmotic dosage form comprising a homogenouscomposition imbibes fluid through the semipermeable wall into the dosageform in response to the concentration gradient across the semipermeablewall. The therapeutic composition in the dosage form develops osmoticenergy that causes the therapeutic composition to be administeredthrough an exit from the dosage form over a prolonged period of time upto 24 hours (or even in some cases up to 30 hours) to provide controlledand sustained prodrug release. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations.

[0297] In another embodiment of the invention, the dosage form comprisesanother osmotic dosage form comprising a wall surrounding a compartment,the wall comprising a semipermeable polymeric composition permeable tothe passage of fluid and substantially impermeable to the passage ofprodrug present in the compartment, a prodrug-containing layercomposition in the compartment, a hydrogel push layer composition in thecompartment comprising an osmotic formulation for imbibing and absorbingfluid for expanding in size for pushing the prodrug composition layerfrom the dosage form, and at least one passageway in the wall forreleasing the prodrug composition. The method delivers the prodrug byimbibing fluid through the semipermeable wall at a fluid imbibing ratedetermined by the permeability of the semipermeable wall and the osmoticpressure across the semipermeable wall causing the push layer to expand,thereby delivering the prodrug from the dosage form through the exitpassageway to a patient over a prolonged period of time (up to 24 oreven 30 hours). The hydrogel layer composition may comprise 10 mg to1000 mg of a hydrogel such as a member selected from the groupconsisting of a polyalkylene oxide of 1,000,000 to 8,000,000 which areselected from the group consisting of a polyethylene oxide of 1,000,000weight-average molecular weight, a polyethylene oxide of 2,000,000molecular weight, a polyethylene oxide of 4,000,000 molecular weight, apolyethylene oxide of 5,000,000 molecular weight, a polyethylene oxideof 7,000,000 molecular weight and a polypropylene oxide of the 1,000,000to 8,000,000 weight-average molecular weight; or 10 mg to 1000 mg of analkali carboxymethylcellulose of 10,000 to 6,000,000 weight averagemolecular weight, such as sodium carboxymethylcellulose or potassiumcarboxymethylcellulose. The hydrogel expansion layer comprises 0.0 mg to350 mg, in present manufacture; 0.1 mg to 250 mg of ahydroxyalkylcellulose of 7,500 to 4,500,00 weight-average molecularweight (e.g., hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxybutylcellulose or hydroxypentylcellulose)in present manufacture; 1 mg to 50 mg of an osmagent selected from thegroup consisting of sodium chloride, potassium chloride, potassium acidphosphate, tartaric acid, citric acid, raffinose, magnesium sulfate,magnesium chloride, urea, inositol, sucrose, glucose and sorbitol; 0 to5 mg of a colorant, such as ferric oxide; 0 mg to 30 mg, in a presentmanufacture, 0.1 mg to 30 mg of a hydroxypropylalkylcellulose of 9,000to 225,000 average-number molecular weight, selected from the groupconsisting of hydroxypropylethylcellulose, hydroxypropypentylcellulose,hydroxypropylmethylcellulose, and hydropropylbutylcellulose; 0.00 to 1.5mg of an antioxidant selected from the group consisting of ascorbicacid, butylated hydroxyanisole, butylatedhydroxyquinone,butylhydroxyanisol, hydroxycomarin, butylated hydroxytoluene, cephalm,ethyl gallate, propyl gallate, octyl gallate, lauryl gallate,propyl-hydroxybenzoae, trihydroxybutylrophenone, dimethylphenol,dibutylphenol, vitamin E, lecithin and ethanolamine; and 0.0 mg to 7 mgof a lubricant selected from the group consisting of calcium stearate,magnesium stearate, zinc stearate, magnesium oleate, calcium palmitate,sodium suberate, potassium laureate, salts of fatty acids, salts ofalicyclic acids, salts of aromatic acids, stearic acid, oleic acid,palmitic acid, a mixture of a salt of a fatty, alicyclic or aromaticacid, and a fatty, alicyclic, or aromatic acid.

[0298] In the osmotic dosage forms, the semipermeable wall comprises acomposition that is permeable to the passage of fluid and impermeable tothe passage of prodrug. The wall is nontoxic and comprises a polymerselected from the group consisting of a cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetateand cellulose triacetate. The wall comprises 75 wt % (weight percent) to100 wt % of the cellulosic wall-forming polymer; or, the wall cancomprise additionally 0.01 wt % to 80 wt % of polyethylene glycol, or 1wt % to 25 wt % of a cellulose ether selected from the group consistingof hydroxypropylcellulose or a hydroxypropylalkycellulose such ashydroxypropylmethylcellulose. The total weight percent of all componentscomprising the wall is equal to 100 wt %. The internal compartmentcomprises the prodrug-containing composition alone or in layeredposition with an expandable hydrogel composition. The expandablehydrogel composition in the compartment increases in dimension byimbibing the fluid through the semipermeable wall, causing the hydrogelto expand and occupy space in the compartment, whereby the drugcomposition is pushed from the dosage form. The therapeutic layer andthe expandable layer act together during the operation of the dosageform for the release of prodrug to a patient over time. The dosage formcomprises a passageway in the wall that connects the exterior of thedosage form with the internal compartment. The osmotic powered dosageform provided by the invention delivers prodrug from the dosage form tothe patient at a zero order rate of release over a period of up to about24 hours.

[0299] The expression “passageway” as used herein comprises means andmethods suitable for the metered release of the prodrug from thecompartment of the dosage form. The exit means comprises at least onepassageway, including orifice, bore, aperture, pore, porous element,hollow fiber, capillary tube, channel, porous overlay, or porous elementthat provides for the osmotic controlled release of prodrug. Thepassageway includes a material that erodes or is leached from the wallin a fluid environment of use to produce at least one controlled-releasedimensioned passageway. Representative materials suitable for forming apassageway, or a multiplicity of passageways comprise a leachablepoly(glycolic) acid or poly(lactic) acid polymer in the wall, agelatinous filament, poly(vinyl alcohol), leach-able polysaccharides,salts, and oxides. A pore passageway, or more than one pore passageway,can be formed by leaching a leachable compound, such as sorbitol, fromthe wall. The passageway possesses controlled-release dimensions, suchas round, triangular, square and elliptical, for the metered release ofprodrug from the dosage form. The dosage form can be constructed withone or more passageways in spaced apart relationship on a single surfaceor on more than one surface of the wall. The expression “fluidenvironment” denotes an aqueous or biological fluid as in a humanpatient, including the gastrointestinal tract. Passageways and equipmentfor forming passageways are disclosed in U.S. Pat. Nos. 3,845,770;3,916,899; 4,063,064; 4,088,864 and 4,816,263. Passageways formed byleaching are disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987.

[0300] Regardless of the specific form of sustained release oral dosageform used, the prodrug is preferably released from the dosage form overa period of at least about 6 hours, more preferably, over a period of atleast about 8 hours, and most preferably, over a period of at leastabout 12 hours. Further, the dosage form preferably releases from 0 to20% of the prodrug in 0 to 2 hours, from 20 to 50% of the prodrug in 2to 12 hours, from 50 to 85% of the prodrug in 3 to 20 hours and greaterthan 75% of the prodrug in 5 to 18 hours. The sustained release oraldosage form further provides a concentration of the GABA analog in theblood plasma of the patient over time, which curve has an area under thecurve (AUC) that is proportional to the dose of the prodrug of GABAanalog administered, and a maximum concentration Cmax. The Cmax is lessthan 75%, and is preferably, less than 60%, of the Cmax obtained fromadministering an equivalent dose of the prodrug from an immediaterelease oral dosage form, and the AUC is substantially the same as theAUC obtained from administering an equivalent dose of the prodrug froman immediate release oral dosage form.

[0301] Preferably, the dosage forms of the invention are administeredtwice per day (more preferably, once per day).

[0302] The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

[0303] In the examples below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning. Atm = atmosphere Boc = tert-butyloxycarbonylCbz = carbobenzyloxy CPM = counts per minute DCC =dicyclohexylcarbodiimide DMAP = 4-N,N-dimethylaminopyridine DMF =N,N-dimethylformamide DMSO = dimethylsulfoxide Fmoc =9-fluorenylmethyloxycarbonyl g = gram h = hour HBSS = Hank's bufferedsaline solution HBTU = O-Benzotriazolyl tetra-N-methyl- = uroniumhexafluorophosphate L = liter LC/MS = liquid chromatography/mass =spectroscopy M = molar min = minute mL = milliliter mmol = millimolesNADPH = nicotinamide-adenine dinucleotide = phosphate NHS =N-hydroxysuccinimide THF = tetrahydrofuran TFA = trifluoroacetic acidTMS = trimethylsilyl μl = microliter μM = micromolar v/v = volume tovolume

[0304] Experimental Methods

Example 1

[0305] Preparation of Aminoacyl-Gabapentin Derivatives—Method 1

[0306] To a 40 mL vial was added an N-Boc-protected amino acid (5 mmol),dicyclohexylcarbodiimide (1.24 g, 6 mmol), N-hydroxysuccinimide (0.7 g,6 mmol), and acetonitrile (20 mL). The reaction mixture was shaken at22-25° C. for 4 h. The precipitated dicyclohexylurea was removed byfiltration. To the filtrate was added an aqueous solution (30 mL) ofgabapentin hydrochloride (1.04 g, 6 mmol), and sodium hydroxide (0.4 g,10 mmol). The reaction was stirred at 22-25 C. for 16 h. The reactionmixture was diluted with ethyl acetate (100 mL) and washed with 0.5 Maqueous citric acid (2×100 mL) and water (2×100 mL). The organic phasewas separated, dried (MgSO₄), filtered and concentrated under reducedpressure. The residue was dissolved in trifluoroacetic acid (40 mL) andallowed to stand at 22-25° C. for 2 h. The solvent was removed underreduced pressure. The residue was dissolved in water (4 mL) and filteredthrough a 0.25 μm nylon membrane filter prior to purification bypreparative HPLC (Phenomenex 250×21.2 mm, 5 μm LUNA C18 column, 100%water for 5 minutes, then 0-60% acetonitrile in water with 0.05% TFAover 20 minutes at 20 mL/min). The pure fractions were combined and thesolvent was removed under reduced pressure to afford the product (1)(typically 70-90%) as a white solid.

[0307] The following compounds were prepared according to the methoddescribed above:

[0308] β-Alanine-Gabapentin (1a): MS (ESI) m/z 241.23 (M−H⁻), 243.26(M+H⁺).

[0309] α-Aminoisobutyryl-Gabapentin (1b): MS (ESI) m/z 255.26 (M−H⁻),257.28 (M+H⁺).

[0310] D-Alanine-Gabapentin (1c): MS (ESI) m/z 241.24 (M−H⁻), 243.27(M+H⁺).

[0311] N-Methyl-Glycine-Gabapentin (1d): MS (ESI) m/z 241.24 (M−H⁻),243.28 (M+H⁺).

[0312] N-Methyl-L-Valine-Gabapentin (1e): MS (ESI) m/z 283.42 (M−H⁻),285.34 (M+H⁺).

[0313] N-Methyl-L-Serine-Gabapentin (1f): MS (ESI) m/z 271.38 (M−H⁻),273.41 (M+H⁺).

[0314] N-Methyl-L-Alanine-Gabapentin (1g): MS (ESI) m/z 255.29 (M−H⁻),257.29 (M+H⁺).

[0315] L-Pipecolyl-Gabapentin (1h): MS (ESI) m/z 281.23 (M−H⁻), 283.15(M+H⁺).

[0316] L-tert-Butylglycine-Gabapentin (1i): MS (ESI) m/z 283.42 (M−H⁻),285.2 (M+H⁺).

[0317] L-2,3-Diaminopropionyl-Gabapentin (1j): MS (ESI) m/z 256.3(M−H⁻), 258.3 (M+H⁺).

[0318] L—Norvaline-Gabapentin (1k): MS (ESI) m/z 269.2 (M−H⁻), 271.24(M+H⁺).

[0319] L-1-Naphthylalanine-Gabapentin (1l): MS (ESI) m/z 367.2 (M−H⁻),369.21 (M+H⁺).

[0320] L-2-Naphthylalanine-Gabapentin (1m): MS (ESI) m/z 367.23 (M−H⁻),369.3 (M+H⁺).

[0321] L-2-Quinoylalanine-Gabapentin (1n): MS (ESI) m/z 368.18 (M−H⁻),370.28 (M+H⁺).

[0322] L-(2-Quinoylalanine N-Oxide)-Gabapentin (1o): MS (ESI) m/z 384.25(M−H⁻), 386.87 (M+H⁺).

[0323] L-2-Pyridylalanine-Gabapentin (1p): MS (ESI) m/z 318.23 (M−H⁻),320.2 (M+H⁺).

[0324] L-3-Pyridylalanine-Gabapentin (1q): MS (ESI) m/z 318.21 (M−H⁻),320.15 (M+H⁺).

[0325] L-(4-Pyridylalanine N-Oxide)-Gabapentin (1r): MS (ESI) m/z 334.24(M−H⁻), 336.24 (M+H⁺).

[0326] L-2-Thienylalanine-Gabapentin (1s): MS (ESI) m/z 323.24 (M−H⁻).

[0327] L-3-Thienylalanine-Gabapentin (1t): MS (ESI) m/z 323.24 (M−H⁻),325.37 (M+H⁺).

[0328] L-3-Benzothienylalanine-Gabapentin (1u): MS (ESI) m/z 373.26(M−H⁻).

[0329] L-4-Thiazolylalanine-Gabapentin (1v): MS (ESI) m/z 324.25 (M−H⁻).

[0330] L-2-Methylphenylalanine-Gabapentin (1w): MS (ESI) m/z 331.28(M−H⁻), 333.6 (M+H⁺).

[0331] L-4-Methylphenylalanine-Gabapentin (1x): MS (ESI) m/z 331.3(M−H⁻).

[0332] L-2-Trifluoromethylphenylalanine-Gabapentin (1y): MS (ESI) m/z385.28 (M−H⁻), 387.61 (M+H⁺).

[0333] L-3-Trifluoromethylphenylalanine-Gabapentin (1z): MS (ESI) m/z385.23 (M−H⁻), 387.63 (M+H⁺).

[0334] L-4-Trifluoromethylphenylalanine-Gabapentin (1aa): MS (ESI) m/z385.26 (M−H⁻).

[0335] L-2-Fluorophenylalanine-Gabapentin (1ab): MS (ESI) m/z 335.2(M−H⁻), 337.19 (M+H⁺).

[0336] L-3-Fluorophenylalanine-Gabapentin (1ac): MS (ESI) m/z 335.19(M−H⁻), 337.15 (M+H⁺).

[0337] L-4-Fluorophenylalanine-Gabapentin (1ad): MS (ESI) m/z 335.16(M−H⁻), 337.21 (M+H⁺).

[0338] L-2-Chlorophenylalanine-Gabapentin (1ae): MS (ESI) m/z 351.14(M−H⁻), 353.1 (M+H⁺).

[0339] L-3-Chlorophenylalanine-Gabapentin (1af): MS (ESI) m/z 351.16(M−H⁻), 353.08 (M+H⁺).

[0340] L-4-Chlorophenylalanine-Gabapentin (1ag): MS (ESI) m/z 351.15(M−H⁻), 353.1 (M+H⁺).

[0341] L-4-Bromophenylalanine-Gabapentin (1ah): MS (ESI) m/z 395.06,397.05 (M−H⁻), 397.02, 399.01 (M+H⁺).

[0342] L-4-Iodophenylalanine-Gabapentin (1ai): MS (ESI) m/z 443.01(M−H⁻), 445.16 (M+H⁺).

[0343] L-2-Methoxyphenylalanine-Gabapentin (1aj): MS (ESI) m/z 347.21(M−H⁻).

[0344] L-4-Methoxyphenylalanine-Gabapentin (1ak): MS (ESI) m/z 347.39(M−H⁻), 349.92 (M+H⁺).

[0345] L-3-Cyanophenylalanine-Gabapentin (1al): MS (ESI) m/z 342.18(M−H⁻), 344.19 (M+H⁺).

[0346] L-4-Cyanophenylalanine-Gabapentin (1am): MS (ESI) m/z 342.2(M−H⁻), 344.09 (M+H⁺).

[0347] L-3,4-Difluorophenylalanine-Gabapentin (1an): MS (ESI) m/z 353.12(M−H⁻), 355.08 (M+H⁺).

[0348] L-3,5-Difluorophenylalanine-Gabapentin (1ao): MS (ESI) m/z 353.17(M−H⁻), 355.18 (M+H⁺).

[0349] D, L-2,4-Difluorophenylalanine-Gabapentin (1ap): MS (ESI) m/z353.14 (M−H⁻).

[0350] D, L-2,6-Difluorophenylalanine-Gabapentin (1aq): MS (ESI) m/z353.18 (M−H⁻), 355.32 (M+H⁺).

[0351] L-2,4-Dichlorophenylalanine-Gabapentin (1ar): MS (ESI) m/z385.26, 387.03 (M−H⁻), 387.47, 389.08 (M+H⁺).

[0352] L-3,4-Dichlorophenylalanine-Gabapentin (1as): MS (ESI) m/z 385.1,387.03 (M−H⁻), 387.07, 388.99 (M+H⁺).

[0353] L-Penicillamine-Gabapentin (1at): MS (ESI) m/z 301.18 (M−H⁻),303.14 (M+H⁺).

[0354] 1-Aminocyclopropane-1-Carbonyl-Gabapentin (1au): MS (ESI) m/z253.23 (M−H⁻), 255.2 (M+H⁺).

[0355] 1-Aminocyclohexane-1-Carbonyl-Gabapentin (1av): MS (ESI) m/z295.24 (M−H⁻), 297.25 (M+H⁺).

[0356] L-Homophenylalanine-Gabapentin (1aw): MS (ESI) m/z 331.15 (M−H⁻).

[0357] L-Serine-Gabapentin (1ax): MS (ESI) m/z 257.11 (M−H⁻), 259.10(M+H⁺).

[0358] Preparation of Aminoacyl-Gabapentin Derivatives—Method 2

[0359] To an ice-cold reaction mixture containing an N-Boc-protectedamino acid (1 mmol) and triethylamine (0.278 mL, 2 mmol) in anhydrousTHF (100 mL) was added ethyl chloroformate (0.115 mL, 1.2 mmol). Thereaction mixture was stirred at 0° C. for 30 min. A solution ofgabapentin hydrochloride salt (311 mg, 1.5 mmol) in 0.5 N NaOH (6 mL)was added at 0° C., stirred for 30 min at 0° C. and then 30 min at roomtemperature. After evaporation of the THF under reduced pressure,saturated citric acid (20 mL) was added. The product was extracted withethyl acetate (3×30 mL) and the combined organic phase dried over MgSO₄and concentrated to dryness. The resulting residue was treated with 80%(v/v) TFA in dichloromethane at room temperature for 30 min. Thereaction mixture was evaporated to dryness. The aminoacyl-Gabapentinproduct was purified by preparative HPLC as described above.

Example 2

[0360] Preparation of Aspartyl-Gabapentin Derivatives

[0361] To a solution of Boc-Asp(OMe)-OH (5 g, 20 mmol) in acetonitrile(100 mL) was added N-hydroxysuccinimide (2.53 g, 22 mmol) andN,N-dicyclohexylcarbodiimide (4.5 g, 22 mmol). The reaction was stirredat ambient temperature for 4 h. The reaction mixture was filtereddirectly into an aqueous solution (100 mL) of gabapentin (3.77 g, 22mmol) and sodium hydrogencarbonate (1.85 g, 22 mmol) and the resultingmixture stirred at ambient temperature for 16 h. The reaction wasconcentrated under reduced pressure, the residue dissolved in ethylacetate/diethyl ether (1:1, 300 mL) and washed with 0.1M aqueouspotassium hydrogensulfate (2×500 mL). The organic phase was separated,dried over Na₂SO₄, filtered, and concentrated to dryness under reducedpressure to afford Boc-Asp(OMe)-Gabapentin as a white solid (7.8 g, 19.5mmol, 98%).

[0362] To 250 mL peptide vessel was added 2-chlorotritylchloride resin(10 g, 1.69 mmol/g, 16.9 mmol), and a solution ofBoc-Asp(OMe)-Gabapentin (7.8 g, 19.5 mmol) in dichloromethane (125 mL).N,N-Diisopropylethylamine (5.2 mL, 30 mmol) was added and the vessel wasshaken at ambient temperature for 1 h. The resin was drained and washedconsecutively with dichloromethane (3×250 mL), methanol (3×250 mL), andtetrahydrofuran (3×250 mL). The resin was shaken with lithium hydroxide(0.5 g) in tetrahydrofuran (100 mL), water (10 mL), and methanol (25 mL)at ambient temperature for 2 h. The resin was drained and washed withmethanol (3×250 mL), dichloromethane (3×250 mL), and N,N-dimethylformide(3×250 mL). The resin was aliquoted into 10 100 mL Alltech tubes and asolution of HBTU (32 g, 84 mmol) in N,N-dimethylacetamide (250 mL) andN,N-diisopropylethylamine (22 mL) was distributed evenly to each vessel.

[0363] To each of the ten vessels was added 5 equivalents of one of thefollowing 10 amines: (a) pyrrolidine; (b) butylamine; (c)2-methoxyethylamine; (d) piperidine; (e) isoamylamine; (f)cyclohexylamine; (g) 4-aminomethylpyridine; (h) 3-aminomethylpyridine;(i) heptylamine; and (j) 3,4-dimethoxyphenethyl-amine. The vessels werecapped and shaken at ambient temperature for 16 h. The resins weredrained and washed with 1-methylpyrrolidinone (3×100 mL), methanol(3×100 mL), and dichloromethane (3×100 mL). The resins were each treatedwith 25% trifluoroacetic acid in dichloromethane (20 mL) for 10 minutes,and drained into 40 mL vials. The solvent was removed under reducedpressure. The residues were dissolved in acetonitrile/water (1:1, 5 mL)and filtered through a 0.2 μm nylon membrane filter. The solutions werepurified by preparative HPLC. The pure fractions were combined andconcentrated under reduced pressure. The pure compounds were redissolvedin 20% acetonitrile in water (10 mL), frozen, and lyophilized to afford15-30 mg of each of the following compounds as white powders:

[0364] L-Aspartyl-β-(Pyrrolidinyl)-Gabapentin (3a): MS (ESI) m/z 338.28(M−H⁻), 340.29 (M+H⁺).

[0365] L-Aspartyl-β-(Butylamido)-Gabapentin (3b): MS (ESI) m/z 340.31(M−H⁻), 342.32 (M+H⁺).

[0366] L-Aspartyl-β-(2-Methoxyethylamido)-Gabapentin (3c): MS (ESI) m/z342.30 (M−H⁻), 344.29 (M+H⁺).

[0367] L-Aspartyl-β-(Piperidinyl)-Gabapentin (3d): MS (ESI) m/z 352.32(M−H⁻), 354.31 (M+H⁺).

[0368] L-Aspartyl-β-(3-Methylbutylamido)-Gabapentin (3e): MS (ESI) m/z354.32 (M−H⁻), 356.37 (M+H⁺).

[0369] L-Aspartyl-β-(Cyclohexylamido)-Gabapentin (3f): MS (ESI) m/z366.33 (M−H⁻), 368.32 (M+H⁺).

[0370] L-Aspartyl-β-(4-Amidomethylpyridine)-Gabapentin (3g): MS (ESI)m/z 375.27 (M−H⁻), 377.29 (M+H⁺).

[0371] L-Aspartyl-β-(3-Amidomethylpyridine)-Gabapentin (3h): MS (ESI)m/z 375.25 (M−H⁻), 377.25 (M+H⁺).

[0372] L-Aspartyl-β-(Heptylamido)-Gabapentin (3i): MS (ESI) m/z 382.32(M−H⁻), 384.42 (M+H+).

[0373] L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Gabapentin (3j): MS(ESI) m/z 448.23 (M−H⁻), 450.27 (M+H⁺).

[0374] L-Aspartyl-β-(O-Cyclohexl ester)-Gabapentin (3k)

[0375] To a solution of L-Boc-Aspartyl-β-(O-Cyclohexyl ester)-OH (1 g,3.2 mmol) in acetonitrile (20 mL) was added N-hydroxysuccinamide (391mg, 3.4 mmol),and N,N-dicyclohexylcarbodiimide (702 mg, 3.4 mmol). Thereaction was shaken at ambient temperature for 4 h. The reaction wasfiltered directly into an aqueous solution (100 mL) of gabapentin (582mg, 3.4 mmol) and sodium hydrogencarbonate (286 mg, 3.4 mmol) and theresulting mixture was shaken at ambient temperature for 16 h. Thereaction was diluted with ethyl acetate/diethyl ether (1:1, 100 mL) andwashed with 0.1M aqueous potassium hydrogensulfate (2×150 mL). Theorganic phase was separated, dried over Na₂SO₄, filtered, andconcentrated to dryness under reduced pressure to afford theL-Boc-Aspartyl-β-(O-Cyclohexyl ester)-Gabapentin as a white solid. Thecompound was dissolved in 33% trifluoroacetic acid in dichloromethane(100 mL) and stirred at ambient temperature for 1 h. The solvent wasremoved under reduced pressure. The residue was dissolved inacetonitrile/water (1:1, 10 mL) and filtered through a 0.2 μm nylonmembrane filter. The solution was purified by preparative HPLC. The purefractions were combined and concentrated under reduced pressure toafford the title compound (3k) as a white powder.

[0376] MS (ESI) m/z 367.39 (M−H⁻), 369.81 (M+H⁺).

[0377] L-Aspartyl-β-(O-Benzyl ester)-Gabapentin (3l)

[0378] To a solution of L-Boc-Aspartyl-β-(O-Benzyl ester)-OH (1 g, 3.2mmol) in acetonitrile (20 mL) was added N-hydroxysuccinamide (391 mg,3.4 mmol),and N,N-dicyclohexylcarbodiimide (702 mg, 3.4 mmol). Thereaction was shaken at ambient temperature for 4 h. The reaction wasfiltered directly into an aqueous solution (100 mL) of gabapentin (582mg, 3.4 mmol) and sodium hydrogencarbonate (286 mg, 3.4 mmol) and theresulting mixture was shaken at ambient temperature for 16 h. Thereaction was diluted with ethyl acetate/diethyl ether (1:1, 100 mL) andwashed with 0.1M aqueous potassium hydrogensulfate (2×150 mL). Theorganic phase was separated, dried over Na₂SO₄, filtered, andconcentrated to dryness under reduced pressure to afford theL-Boc-Aspartyl-β-(O-Benzyl ester)-Gabapentin as a white solid. Thecompound was dissolved in 33% trifluoroacetic acid in dichloromethane(100 mL) and stirred at ambient temperature for 1 h. The solvent wasremoved under reduced pressure. The residue was dissolved inacetonitrile/water (1:1, 10 mL) and filtered through a 0.2 μm nylonmembrane filter. The solution was purified by preparative HPLC. The purefractions were combined and concentrated under reduced pressure toafford the title compound (31) as a white powder.

[0379] MS (ESI) m/z 375.28 (M−H⁻), 377.65 (M+H⁺).

Example 3

[0380] Preparation of Tyrosine-Gabapentin Derivatives

[0381] To a solution of Boc-Tyr-OH (4.2 g, 15 mmol) in acetonitrile (100mL) was added N-hydroxysuccinamide (1.84 g, 16 mmol) andN,N-dicyclohexylcarbodiimide (3.3 g, 16 mmol). The reaction was stirredat ambient temperature for 2 h. The reaction mixture was filtereddirectly into an aqueous solution (100 mL) of gabapentin (2.7 g, 16mmol) and sodium hydroxide (640 mg, 16 mmol), and the resulting mixturestirred at ambient temperature for 16 h. The reaction was concentratedunder reduced pressure, the residue was dissolved in ethylacetate/diethyl ether (1/1, 200 mL) and washed with 0.1M aqueouspotassium hydrogensulfate (2×200 mL). The organic phase was separated,dried over Na₂SO₄, filtered, and concentrated to dryness under reducedpressure to afford Boc-Tyr-Gabapentin as a white solid (7.4 g, 16 mmol).

[0382] Boc-Tyr-Gabapentin (434 mg, 1 mmol) was treated withtrifluoroacetic acid (10 mL) at ambient temperature for 1 h, followed bythe addition of an acid chloride, symmetrical anhydride or chloroformate(0.9 mmol). The reactions were stirred at ambient temperature for 1 h.The solvent was removed under reduced pressure and the residuesdissolved in acetonitrile/water (1:1, 5 mL) and filtered through a 0.2μm nylon membrane filter. The solutions were purified by preparativeHPLC. The pure fractions were combined and concentrated under reducedpressure to afford each of the following compounds as colorless syrups:

[0383] L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Gabapentin (4a): MS (ESI) m/z465.33 (M−H⁻), 467.33 (M+H⁺).

[0384] L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Gabapentin (4b): MS (ESI) m/z497.34 (M−H⁻), 499.30 (M+H⁺).

[0385] L-Tyrosine-(O-2-Methylbenzoyl)-Gabapentin (4c): MS (ESI) m/z451.31 (M−H⁻), 453.35 (M+H⁺).

[0386] L-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Gabapentin (4d): MS (ESI)m/z 544.12, 546.14 (M−H⁻), 546.15, 548.16 (M+H⁺).

Example 4

[0387] Preparation of L-4-Bromophenylalanine-Pregabalin (5)

[0388] A suspension of L-Boc-4-bromophenylalanine (500 mg, 1.46 mmol),N-hydroxysuccinimide (173 mg, 1.50 mmol), N,N-dicyclohexylcarbodiimide(310 mg, 1.50 mmol) in acetonitrile was stirred at room temperature for1 h. Then the reaction mixture was filtered directly into a stirredaqueous solution of pregabalin (239 mg, 1.50 mmol) and NaOH (60 mg, 1.5mmol). The resulting mixture was stirred for another hour at roomtemperature. After removing the organic solvent under reduced pressure,the aqueous solution was acidified to pH 3 with KHSO₄ and the resultingmixture was extracted with ethyl acetate:ether (1:2). The organicextract was washed with brine and dried over Na₂SO₄. After removing thesolvent under reduced pressure, the residue was dissolved in 4N HCl indioxane (10 mL) and stirred at room temperature for 2 h. The solutionwas concentrated under reduced pressure to afford white precipitate.Re-crystallization from hot water followed by HPLC purification afforded412 mg of the title compound (5). ¹H-NMR (CD₃OD, 400 MHz): δ0.86 (d,J=6.8 Hz, 3 H), 0.89 (d, J=6.8 Hz, 3H), 1.06 (m, 2H), 1.64 (m, 1H),2.08−2.00 (m, 3H), 3.00 (m, 2H), 3.12 (dd, J=14.0, 7.4 Hz, 1H), 3.25(overlapped with methanol, 1H), 3.95 (m, 1H), 7.19 (d, J=8.0 Hz, 2H),7.50 (d, J=8 Hz, 2H).

Example 5

[0389] In Vitro Compound Transport Assays with PEPT1 andPEPT2-Expressing Cell Lines

[0390] (a) Inhibition of Radiolabeled Gly-Sar Uptake

[0391] Rat and human PEPT1 and PEPT2 expressing CHO cell lines wereprepared as described in PCT Application WO01/20331.Gabapentin-containing dipeptides were evaluated for interaction with thepeptide transporters using a radiolabeled substrate uptake assay in acompetitive inhibition format, as described in PCT ApplicationWO01/20331. Transport-induced currents were also measured in Xenopusoocytes transfected with rat and human PEPT1 and PEPT2.

[0392] (b) Analysis of Electrogenic Transport in Xenopus oocytes

[0393] RNA preparation: Rat and human PEPT1 and PEPT2 transporter cDNAswere subcloned into a modified pGEM plasmid that contains 5′ and 3′untranslated sequences from the Xenopus β-actin gene. These sequencesincrease RNA stability and protein expression. Plasmid cDNA waslinearized and used as template for in vitro transcription (EpicentreTechnologies transcription kit, 4:1 methylated:non-methylated GTP).

[0394]Xenopus oocyte isolation. Xenopus laevis frogs were anesthetizedby immersion in Tricaine (1.5 g/mL in deionized water) for 15 min.Oocytes were removed and digested in frog ringer solution (90 mM NaCl, 2mM KCl, 1 mM MgCl₂, 10 mM NaHEPES, pH 7.45, no CaCl₂) with 1 mg/mLcollagenase (Worthington Type 3) for 80-100 min with shaking. Theoocytes were washed 6 times, and the buffer changed to frog ringersolution containing CaCl₂ (1.8 mM). Remaining follicle cells wereremoved if necessary. Cells were incubated at 16° C., and each oocyteinjected with 10-20 μg RNA in 45 μL solution.

[0395] Electrophysiology measurements. Transport currents were measured2-14 days after injection, using a standard two-electrodeelectrophysiology set-up (Geneclamp 500 amplifier, Digidata 1320/PCLAMPsoftware and ADInstruments hardware and software were used for signalacquisition). Electrodes (2-4 mΩ) were microfabricated using a SutterInstrument puller and filled with 3M KCl. The bath was directly grounded(transporter currents were less than 0.3 μA). Bath flow was controlledby an automated perfusion system (ALA Scientific Instruments, solenoidvalves). For transporter pharmacology, oocytes were clamped at −60 to−90 mV, and continuous current measurements acquired using PowerLabSoftware and an ADInstruments digitizer. Current signals were lowpassfiltered at 20 Hz and acquired at 4-8 Hz. All bath and drug-containingsolutions were frog ringers solution containing CaCl₂. Drugs wereapplied for 10-30 seconds until the induced current reached a newsteady-state level, followed by a control solution until baselinecurrents returned to levels that preceded drug application. Thedifference current (baseline subtracted from peak current during drugapplication) reflected the net movement of charge resulting fromelectrogenic transport and was directly proportional to transport rate.Recordings were made from a single oocyte for up to 60 min, enabling30-40 separate compounds to be tested per oocyte. Compound-inducedcurrents were saturable and gave half-maximal values at substrateconcentrations comparable to radiolabel competition experiments. Tocompare results between oocytes expressing different levels of transportactivity, a saturating concentration of glycyl-sarcosine (1 mM) was usedas a common reference to normalize results from test compounds. Usingthis normalization procedure I_(max) (i.e. maximal induced current) fordifferent compounds tested on different oocytes could be compared.

[0396] Each of the compounds (1a)-(1ax), (3a)-(3l) and (5) elicitedPEPT-specific currents significantly above background (at least 5% ofI_(max) for Gly-Sar) when tested at 1 mM on oocytes expressing eitherPEPT1 or PEPT2, confirming that these compounds serve as substrates forboth of these transporters.

Example 6

[0397] In Vitro Enzymatic Release of Gabapentin fromAminoacyl-Gabapentin Conjugates

[0398] The stability of aminoacyl-gabapentin conjugates was evaluated byincubating the conjugates in the various tissue and enzyme-containingpreparations listed in Table 1 below.

[0399] Tissue homogenates and plasma samples were obtained fromcommercial sources (Pel-Freez Biologicals, Rogers, Ariz., and GenTestCorporation, Woburn, Mass.). Stability of prodrugs toward the specificenzyme aminopeptidase was also evaluated by incubation with the purifiedenzyme. Experimental conditions used for the in vitro studies were asfollows. Each preparation was incubated with test compound at 37° C. forone hour. Aliquots (50 μL) were removed at 0, 30, and 60 min andquenched with 0.1% trifluoroacetic acid in acetonitrile. Samples werethen centrifuged and analyzed for the presence of prodrug and releasedgabapentin by LC/MS/MS as described below.

[0400] Rat intestinal wash is obtained from rats post-morten by rinsingthe surgically separated intesting with small volumes (about 3 mL) ofbuffered saline.

[0401] Concentrations of prodrug or gabapentin in tissue extracts weredetermined by direct injection onto an API 2000 LC/MS/MS equipped withan Agilent 1100 binary pump and autosampler. Separation was achievedusing a 3.5 μm Zorbax Ellipse XDB-C8 4.4×150 mm column heated to 45° C.during the analysis. The mobile phases were: 0.1% formic acid in water(A) and 0.1% formic acid in acetonitrile (B). The gradient conditionwas: 2% B for 0.5 min, increasing to 90% B in 2.0 min, maintained for2.5 min and returning to 2% B for 2 min. A TurboIonSpray source was usedon the API 2000. The analysis was performed in the positive ion mode andMRM transitions of 172.0/137.2 were used in the analysis of gabapentin(2). Ten microliters of the sample extracts were injected. Peaks wereintegrated using Analyst quantitation software. The method was linearfor (2) over the concentration range 0.002 to 2.5 μg/mL respectively.

[0402] The stability of gabapentin-containing prodrugs to Caco-2homogenates was evaluated as follows:

[0403] Caco-2 Homogenate S9 Stability: Caco-2 cells were grown for 21days prior to harvesting. Culture medium was removed and cell monolayerswere rinsed and scraped off into ice-cold 10 mM sodium phosphate/0.15 Mpotassium chloride, pH 7.4. Cells were lysed by sonication at 4° C.using a probe sonicator. Lysed cells were then transferred into 1.5 mLcentrifuge vials and centrifuged at 9000 g for 20 min at 4° C. Theresulting supernatant (Caco-2 cell homogenate S9 fraction) was aliquotedinto 0.5 mL vials and stored at −80° C. until used.

[0404] For stability studies, prodrug (5 μM) was incubated in Caco-2homogenate S9 fraction (0.5 mg protein per mL) for 60 min at 37° C.Concentrations of intact prodrug and released drug were determined atzero time and 60 minutes using LC/MS/MS.

[0405] Aminopeptidase Stability: Aminopeptidase 1 (Sigma catalog #A-9934) was diluted in deionised water to a concentration of 856units/mL. Stability studies were conducted by incubating prodrug (5 μM)with 0.856 units/mL aminopeptidase 1 in 50 mM Tris-HCl buffer at pH 8.0and 37° C. Concentrations of intact prodrug and released drug weredetermined at zero time and 60 minutes using LC/MS/MS.

[0406] Table 1: Experimental Conditions for In Vitro Enzymatic Releaseof Gabapentin in 60 Minutes from Aminoacyl-Gabapentin Prodrugs SubstratePreparation Concentration Cofactors Rat Plasma 2.0 μM None Human Plasma2.0 μM None Rat Liver S9 2.0 μM NADPH (0.5 mg/mL) Human Liver 2.0 μMNADPH S9 (0.5 mg/mL) Human 2.0 μM NADPH Intestine S9 (0.5 mg/mL) RatIntestinal 5.0 μM None Wash Caco-2 5.0 μM None Homogenate Amino- 5.0 μMNone peptidase

[0407] Each of the compounds (1h)-(1aw) showed either partial orcomplete conversion to gabapentin (2) when treated with either Caco-2homogenate or aminopeptidase under the conditions described above.

[0408] Incubation with Caco-2 homogenate for 1 hour resulted inmetabolism of >50% of the following compounds (% of prodrug survivingintact in parenthesis): (1l) (29%); (1al) (46%); (1ao) (48%); (4d) (3%).

[0409] Incubation with Caco-2 homogenate for 1 hour resulted inmetabolism of <50% of the following compounds (% of prodrug survivingintact in parenthesis): (1aa) (97%); (1ah) (79%); (1am) (90%); (1ap)(90%).

Example 7

[0410] Uptake of Gabapentin (2) Following Oral Administration ofProdrugsto Rats

[0411] The pharmacokinetics of the prodrugs prepared in Examples 1 and 3were examined in rats. Three groups of four male Sprague-Dawley rats(approx 200 g) with jugular cannulae each received one of the followingtreatments: A) a single bolus intravenous injection of gabapentin (25mg/kg, as a solution in water); B) a single oral dose of gabapentin (25mg/kg, as a solution in water) administered by oral gavage; C) a singleoral dose of prodrug (25 mg-equivalents of gabapentin per kg bodyweight, as a solution in water) administered by oral gavage. Animalswere fasted overnight prior to dosing and until 4 hours post-dosing.Serial blood samples were obtained over 24 hours following dosing andblood was processed for plasma by centrifugation. Plasma samples werestored at −80° C. until analyzed.

[0412] Concentrations of prodrug or gabapentin in plasma samples weredetermined by LC/MS/MS as described above. Plasma (50 μL) wasprecipitated by addition of 100 mL of methanol and supernatant wasinjected directly onto the LC/MS/MS system. Following oraladministration of gabapentin, concentrations of gabapentin in plasmareached a maximum plasma concentration (C_(max)) of 10.3 μg/mL anddeclined thereafter with a terminal half-life of 2.4±0.5 hours. The oralbioavailability of gabapentin was 87±18%. Following oral administrationof gabapentin prodrugs, concentrations of prodrug and gabapentin inplasma were monitored over 24 hours. The C_(max) values for prodrug(C_(max) PD) were as follows:

[0413] (1l) C_(max)PD=0.5 μg/mL

[0414] (1al) C_(max)PD=0.6 μg/mL

[0415] (1ao) C_(max)PD=2.9 μg/mL

[0416] (4d) C_(max)PD=<0.004 μg/mL

[0417] (1aa) C_(max)PD=30.0 μg/mL

[0418] (1ah) C_(max)PD=103 μg/mL

[0419] (1am) C_(max)PD=22.4 μg/mL

[0420] (1ap) C_(max)PD=278 μg/mL

[0421] This data indicates that gabapentin prodrugs which undergosubstantial (i.e >50%) degradation in the presence of enterocyte(Caco-2) homogenate over a period of 1 h in vitro (e.g. (1l), (1al),(1ao) and (4d)) produce low maximal plasma prodrug concentrationsfollowing oral administration to rats. This is likely due to presystemichydrolysis (or other metabolism) of the prodrug, either within theintestinal lumen, at the enterocyte brush-border membrane orintracellularly (within enterocytes lining the GI tract).

[0422] The C_(max) value for gabapentin following oral administration of(1ah) was 6.1 μg/mL, and its oral bioavailability (F) as gabapentin was53%. Prodrugs of gabapentin have an oral bioavailability (F) asgabapentin preferably of at least 40%, more preferably of at least 50%,and most preferably of at least 75%.

Example 8

[0423] Uptake of Gabapentin (2) Following Oral Administration of (1ax)to Monkeys and Rats

[0424] The pharmacokinetics of prodrug (1ax) was examined in adult malecynomologous monkeys. The prodrug was administered orally to four adultmale monkeys (approximate body weight of 6.5 kg) via an oral nasogastrictubeas solutions in water or PEG 400. The dose was 10 or 75mg-equivalents of gabapentin per kg body weight. Animals were fastedovernight before the study and for 4 hours post-dosing. Blood samples(1.0 mL) were obtained via femoral or cephalic venipuncture at intervalsover 48 hours after oral dosing. Blood was processed immediately forplasma and plasma was frozen at −80° C. until analyzed. Concentrationsof (1ax) or gabapentin (2) in plasma samples were determined by LC/MS/MSas previously described, using MRM transitions of 259.20/154.00 foranalysis of (1ax). Oral bioavailability was determined by comparison ofarea under the gabapentin concentration versus time curve (AUC)following oral administration of prodrug or intravenous administrationof an equimolar dose of gabapentin hydrochloride. The C_(max) and AUCvalues for gabapentin (2) (C_(max) G; AUC G), and the oralbioavailability as gabapentin (F) for each treatment were as follows:

[0425] (2) at 10 mg-eg/kg: C_(max)G=3.7±1.6 μg/mL; AUC G=32.1±10.4μg.h/mL; F=53.9±17.3%.

[0426] (1ax) at 10 mg-eg/kg: C_(max)G=3.7±1.1 μg/mL; AUC G=24.7±7.3μg.h/mL; F=41.5±12.2%.

[0427] (2) at 75 mg-eg/kg: C_(max)G=10.8±1.3 μg/mL; AUC G=102±4.9μg.h/mL; F=22.9±1.1%.

[0428] (1ax) at 75 mg-eg/kg: C_(max)G=14.5±1.6 μg/mL; AUC G=125±5.0μg.h/mL; F=28.1±1.1%.

[0429] This data shows a statistically significant increase (p<0.05) inboth C_(max) and AUC for gabapentin after oral administration as theprodrug (1ax), as compared to dosing of an equimolar amount ofgabapentin (2) itself at the high dose (75 mg-eq./kg) level. A 7.5-foldincrease in gabapentin dose results in only a 3.2-fold increase ingabapentin exposure (as measured by AUC), while a 7.5-fold increase inprodrug dose results in a 5.1-fold increase in gabapentin exposure (asmeasured by AUC). Thus the less than dose-proportional increase ingabapentin exposure observed following gabapentin dosing at levelssufficient to saturate the drug's normal uptake pathway can be offset,in part, by administering a prodrug that exploits a higher capacityuptake mechanism (e.g. the PEPT transporter).

[0430] However, oral and i.v. dosing of prodrug (1ax) to rats hasdemonstrated that the fraction of (1ax) absorbed intact following oraladministration is only about 15-20%, indicating that the majority of theprodrug is hydrolyzed to gabapentin presystemically (probably within theintestinal lumen). This presystemically generated gabapentin is subjectto absorption via the same saturable pathway normally used bygabapentin. This data is consistent with the less than fulldose-proportional increase in gabapentin exposure observed followingprodrug (1ax) dose acsension in monkeys, since it is likely that only afraction of the prodrug survived intra-lumenally to take advantage of ahigher capacity uptake pathway via the peptide transporter.

[0431] In contrast to (1ax), oral and i.v. dosing of prodrug (1ah) torats has demonstrated that the fraction of (1ah) absorbed intactfollowing oral administration is about 60%, with the prodrug convertingrapidly to (2) within the systemic circulation and providing gabapentinwith an oral bioavailability of about 53%. Thus the4-bromophenylalanine-containing gabapentin dipeptide is a more preferredprodrug than the serine compound for exploiting the greater uptakecapacity of intestinal peptide transporters.

Example 9

[0432] Uptake of Gabapentin (2) Following Oral Administration of (1ah)to Monkeys

[0433] The pharmacokinetics of the prodrug (1ah) was examined in adultmale cynomologous monkeys. The prodrug was administered as its sodiumsalt orally to four adult male monkeys (approximate body weight of 6.5kg) via an oral nasogastric tubeas solutions in water. The dose was 10mg-equivalents of gabapentin per kg body weight. Animals were fastedovernight before the study and for 4 hours post-dosing. Blood samples(1.0 mL) were obtained via femoral or cephalic venipuncture at intervalsover 48 hours after oral dosing. Blood was processed immediately forplasma and plasma was frozen at −80° C. until analyzed. Concentrationsof (1ah) and (2) in plasma samples were determined by LC/MS/MS aspreviously described, using MRM transitions of 399.07/200.02 foranalysis of (1ah). Oral bioavailability was determined by comparison ofarea under the gabapentin concentration versus time curve (AUC)following oral administration of prodrug or intravenous administrationof an equimolar dose of gabapentin hydrochloride. Pharmacokineticparameters for (1ah) were as follows:

[0434] C_(max)G=3.8±1.1 μg/mL; AUC G=29.1±3.5 μg.h/mL;C_(max)PH=14.9±5.3 μg/mL;

[0435] AUC PD=18.9±6.5 μg.h/mL; F=49.1±6.8%

[0436] This data corroborates in monkeys the finding from rats that(1ah) is effectively absorbed intact after oral dosing and undergoesrapid conversion to gabapentin.

Example 10

[0437] Uptake of Gabapentin Following Administration of Gabapentin orProdrug (1ah) Intracolonically in Rats

[0438] Sustained release oral dosage forms, which release drug slowlyover periods of 6-24 hours, generally release a significant proportionof the dose within the colon. Thus drugs suitable for use in such dosageforms preferably exhibit good colonic absorption. This experiment wasconducted to assess the suitability of a gabapentin prodrug ((1ah)) foruse in an oral sustained release dosage form.

[0439] Rats were obtained commercially and were pre-cannulated in theboth the ascending colon and the jugular vein. Animals were conscious atthe time of the experiment. All animals were fasted overnight and until4 hours post-dosing. Gabapentin or (1ah) (as the sodium salt) wereadministered as solutions in water directly into the colon via thecannula at a dose equivalent to 25 mg of gabapentin per kg. Bloodsamples (0.5 mL) were obtained from the jugular cannula at intervalsover 8 hours and were quenched immediately by addition ofacetonitrile/methanol to prevent further conversion of the prodrug.Blood was processed for plasma by centrifugation and concentrations ofprodrug (1ah) or (2) in plasma samples were determined by LC/MS/MS aspreviously described. Following colonic administration of (1ah) themaximum plasma concentrations of gabapentin, as well as the area underthe gabapentin plasma concentration vs. time curves, were significantlygreater (>3-fold) than that produced from colonic administration ofgabapentin itself.

[0440] This data demonstrates that compounds of the invention may beformulated as compositions suitable for enhanced absorption and/oreffective sustained release of GABA analogs to minimize dosing frequencydue to rapid systemic clearance of these GABA analogs.

What is claimed is:
 1. A GABA analog derivative comprising a compound ofFormula (I): H—I_(i)-J_(j)-D-K_(k)—OH   (I) wherein: H is hydrogen; I is—[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—; J is—[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—; K is—[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—; wherein a, b, c, d, e and fare independently 0 or 1, provided that at least one of a and b is 1, atleast one of c and d is 1, and at least one of e and f is 1; and whereini, j and k are independently 0 or 1, provided that at least one of i, jand k is 1; D is a moiety derived from a GABA analog having thefollowing structure:

wherein: R³ is a covalent bond linking the GABA analog moiety to J_(j);R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring; R⁵ and R⁶ are independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl,or R⁷ and R⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring; R⁹ is selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl,heteroaryl and substituted heteroaryl; R¹⁰ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl; R¹¹ isC(O)R¹², wherein R¹² is a covalent bond linking the moiety derived froma GABA analog to K_(k); R⁵⁰ is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁰ and R⁵¹ together with theatoms to which they are attached form a heterocyclyl ring; R⁵¹ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁵³ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵³ and R⁵⁴ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁵⁴ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵⁵ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵⁵ and R⁵⁶, together with the atoms to whichthey are attached form a heterocyclyl ring; R⁵⁶ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁵⁶ and R⁵⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R⁵⁶ and R⁵⁸ together with the atoms to which theyare attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R⁵⁷ is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶⁰ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁶⁰ and R⁶¹,together with the atoms to which they are attached form a heterocyclylring; R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶³ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶³ and R⁶⁴ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁶⁴ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; and pharmaceutically acceptable salts, hydrates and solvatesthereof, provided that if k is 0 then neither I nor J is derived fromalanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine, valine or phenylglycine; and provided that when R⁵, R⁶, R⁹ andR¹⁰ are each hydrogen, then R⁷ and R⁸ are neither both hydrogen nor bothmethyl; and yet further provided that when D is either of the followingmoieties

neither I nor J are selected from the group of moieties consisting of:H₂NCH₂C(O)—, H₂NCH(CH₃)C(O)—, NH₂CH₂CH₂C(O)— and


2. The compound according to claim 1, wherein i and k are 0, and j is 1.3. The compound according to claim 1, wherein k is 0, and i and j are 1.4. The compound according to claim 1, wherein i is 0, and j and k are 1.5. The compound according to claim 1, wherein a and c are 1, and b and dare
 0. 6. The compound according to claim 1, wherein I, J and K are notderived from natural amino acids.
 7. The compound according to claim 1,wherein at least one of I, J and K are derived from the group consistingof O-phosphoserine and O-phosphotyrosine.
 8. The compound according toclaim 5, wherein i and k are 0, and j is
 1. 9. The compound of claim 1,wherein D is a moiety selected from the group consisting of thefollowing GABA analog moieties:


10. The compound of claims 1, wherein D is a moiety selected from thegroup consisting of the following GABA analog moieties:


11. The compound of claim 9, wherein i and k are 0, j is 1, c is 1, andd is
 0. 12. The compound of claim 11, wherein R⁵⁵ is hydrogen; R⁵⁷ ishydrogen; and R⁵⁶ is selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl.
 13. The compound of claim 12, wherein R⁵⁶ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, aryl, substituted aryl and heteroaryl.
 14. Thecompound of claim 11, wherein R⁵⁷ is hydrogen; and R⁵⁵ and R⁵⁶ togetherwith the atoms to which they are attached form a heterocyclyl orsubstituted heterocyclyl ring.
 15. The compound of claim 14, wherein R⁵⁵and R⁵⁶ together with the atoms to which they are attached form anazetidine, 4-substituted pyrrolidine, piperidine or substitutedpiperidine ring.
 16. The compound of claim 11, wherein R⁵⁵ is hydrogen;and R⁵⁶ and R⁵⁷ together with the atoms to which they are attached forma cycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring.
 17. The compound of claim 16, wherein R⁵⁶ and R⁵⁷together with the atoms to which they are attached form a cyclopropyl,cyclobutyl, cyclopentyl, substituted cyclopentyl cyclohexyl, substitutedcyclohexyl, piperidinyl or substituted piperidinyl ring.
 18. Thecompound of claim 12, wherein R⁵⁶ is substituted alkyl.
 19. The compoundof claim 18, wherein R⁵⁶ is selected from the group consisting ofarylalkyl, substituted arylalkyl, heteroarylalkyl and substitutedheteroarylalkyl.
 20. The compound of claim 19, wherein R⁵⁶ is selectedfrom the group consisting of substituted benzyl, s-naphthylmethyl,substituted s-naphthylmethyl, t-pyridylmethyl, substitutedt-pyridylmethyl, t-quinolylmethyl, substituted t-quinolylmethyl,u-furanylmethyl, substituted u-furanylmethyl, u-benzofuranylmethyl,substituted u-benzofuranylmethyl, u-thienylmethyl, substitutedu-thienylmethyl, u-benzothienylmethyl, substituted u-benzothienylmethyl,u-pyrrolylmethyl, substituted u-pyrrolylmethyl, substitutedu-indolylmethyl, u-pyrazinylmethyl, substituted u-pyrazinylmethyl,substituted v-imidazolylmethyl, v-oxazolylmethyl, substitutedv-oxazolylmethyl, v-thiazolylmethyl and substituted v-thiazolylmethyl;and wherein s is 1 or 2; t is 2, 3 or 4; u is 2or 3; and .v is 2, 4 or5.
 21. The compound of claim 20, wherein R⁵⁶ is selected from the groupconsisting of 2-methylphenylmethyl, 3-methylphenylmethyl,4-methylphenylmethyl, 2-methoxyphenylmethyl, 3-methoxyphenylmethyl,4-methoxyphenylmethyl, 2-trifluoromethylphenylmethyl,3-trifluoromethylphenylmethyl, 4-trifluoromethylphenylmethyl,2-cyanophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl,2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl,2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl,2-bromophenylmethyl, 3-bromophenylmethyl, 4-bromophenylmethyl,2-iodophenylmethyl, 3-iodophenylmethyl, 4-iodophenylmethyl,2,3-difluorophenylmethyl, 2,4-difluorophenylmethyl,2,5-difluorophenylmethyl, 2,6-difluorophenylmethyl,3,4-difluorophenylmethyl, 3,5-difluorophenylmethyl,2,3-dichlorophenylmethyl, 2,4-dichlorophenylmethyl,2,5-dichlorophenylmethyl, 2,6-dichlorophenylmethyl,3,4-dichlorophenylmethyl, 3,5-dichlorophenylmethyl, 1-naphthylmethyl,2-naphthylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-quinolylmethyl, 3-quinolylmethyl, 4-quinolylmethyl, 2-furanylmethyl,3-furanylmethyl, 3-benzofuranylmethyl, 2-thienylmethyl, 3-thienylmethyl,3-benzothienylmethyl, 5-hydroxyindol-3-ylmethyl,5-alkoxyindol-3-ylmethyl, 5-acyloxyindol-3-ylmethyl, 2-oxazolylmethyl,4-oxazolylmethyl 2-thiazolylmethyl and 4-thiazolylmethyl.
 22. Thecompound of claim 18, wherein R⁵⁶ is selected from the group consistingof —(CH₂)_(n)C(O)XR¹³ and —CH₂[4-C₆H₄—OC(O)R¹⁵]; and wherein: n is 1 or2; X is 0 or NR¹⁴; R¹³ and R¹⁴ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R¹³ and R¹⁴ togetherwith the atoms to which they are attached form a heterocyclyl orsubstituted heterocyclyl ring; and R¹⁵ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy,alkenyloxy, substituted alkenyloxy, alkynyloxy, substituted alkynyloxy,cycloalkoxy, substituted cycloalkoxy, heterocyclyloxy, substitutedheterocyclyloxy, aryloxy, substituted aryloxy, heteroaryloxy andsubstituted heteroaryloxy; provided that when X is O, then R¹³ is nothydrogen; and when X is NR¹⁴, then R¹³ and R¹⁴ are not both hydrogen.23. A GABA analog derivative comprising a compound selected from thegroup consisting of L-1-Naphthylalanine-Gabapentin,L-2-Naphthylalanine-Gabapentin, L-2-Quinoylalanine-Gabapentin,L-(2-Quinoylalanine N-Oxide)-Gabapentin, L-2-Pyridylalanine-Gabapentin,L-3-Pyridylalanine-Gabapentin, L-(4-Pyridylalanine N-Oxide)-Gabapentin,L-2-Thienylalanine-Gabapentin, L-3-Thienylalanine-Gabapentin,L-3-Benzothienylalanine-Gabapentin, L-4-Thiazolylalanine-Gabapentin,L-2-Methylphenylalanine-Gabapentin, L-4-Methylphenylalanine-Gabapentin,L-2-Trifluoromethylphenylalanine-Gabapentin,L-3-Trifluoromethylphenylalanine-Gabapentin,L-4-Trifluoromethylphenylalanine-Gabapentin,L-2-Fluorophenylalanine-Gabapentin, L-3-Fluorophenylalanine-Gabapentin,L-4-Fluorophenylalanine-Gabapentin, L-2-Chlorophenylalanine-Gabapentin,L-3-Chlorophenylalanine-Gabapentin, L-4-Chlorophenylalanine-Gabapentin,L-4-Bromophenylalanine-Gabapentin, L-4-Iodophenylalanine-Gabapentin,L-2-Methoxyphenylalanine-Gabapentin,L-4-Methoxyphenylalanine-Gabapentin, L-4-Ethoxyphenylalanine-Gabapentin,L-3-Cyanophenylalanine-Gabapentin, L-4-Cyanophenylalanine-Gabapentin,L-3,4-Difluorophenylalanine-Gabapentin,L-3,5-Difluorophenylalanine-Gabapentin, D,L-2,4-Difluorophenylalanine-Gabapentin, D,L-2,6-Difluorophenylalanine-Gabapentin,L-2,4-Dichlorophenylalanine-Gabapentin,L-3,4-Dichlorophenylalanine-Gabapentin, L-Pipecolyl-Gabapentin,L-tert-Butylglycine-Gabapentin, L-2,3-Diaminopropionyl-Gabapentin,L-Norvaline-Gabapentin, L-Penicillamine-Gabapentin,1-Aminocyclopropane-1-Carbonyl-Gabapentin,1-Aminocyclohexane-1-Carbonyl-Gabapentin,L-Homophenylalanine-Gabapentin, L-Aspartyl-β-(Pyrrolidinyl)-Gabapentin,L-Aspartyl-β-(Butylamido)-Gabapentin,L-Aspartyl-β-(2-Methoxyethylamido)-Gabapentin,L-Aspartyl-β-(Piperidinyl)-Gabapentin,L-Aspartyl-β-(3-Methylbutylamido)-Gabapentin,L-Aspartyl-β-(Cyclohexylamido)-Gabapentin,L-Aspartyl-β-(4-Amidomethylpyridine)-Gabapentin,L-Aspartyl-β-(3-Amidomethylpyridine)-Gabapentin,L-Aspartyl-β-(Heptylamido)-Gabapentin,L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Gabapentin,L-Aspartyl-β-(O-Cyclohexyl ester)-Gabapentin, L-Aspartyl-β-(O-Benzylester)-Gabapentin, L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Gabapentin,L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Gabapentin,L-Tyrosine-(O-2-Methylbenzoyl)-Gabapentin andL-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Gabapentin.
 24. A GABA analogderivative comprising a compound selected from the group consisting ofL-1-Naphthylalanine-Pregabalin, L-2-Naphthylalanine-Pregabalin,L-2-Quinoylalanine-Pregabalin, L-(2-Quinoylalanine N-Oxide)-Pregabalin,L-2-Pyridylalanine-Pregabalin, L-3-Pyridylalanine-Pregabalin,L-(4-Pyridylalanine N-Oxide)-Pregabalin, L-2-Thienylalanine-Pregabalin,L-3-Thienylalanine-Pregabalin, L-3-Benzothienylalanine-Pregabalin,L-4-Thiazolylalanine-Pregabalin, L-2-Methylphenylalanine-Pregabalin,L-4-Methylphenylalanine-Pregabalin,L-2-Trifluoromethylphenylalanine-Pregabalin,L-3-Trifluoromethylphenylalanine-Pregabalin,L-4-Trifluoromethylphenylalanine-Pregabalin,L-2-Fluorophenylalanine-Pregabalin, L-3-Fluorophenylalanine-Pregabalin,L-4-Fluorophenylalanine-Pregabalin, L-2-Chlorophenylalanine-Pregabalin,L-3-Chlorophenylalanine-Pregabalin, L-4-Chlorophenylalanine-Pregabalin,L-4-Bromophenylalanine-Pregabalin, L-4-Iodophenylalanine-Pregabalin,L-2-Methoxyphenylalanine-Pregabalin,L-4-Methoxyphenylalanine-Pregabalin, L-4-Ethoxyphenylalanine-Pregabalin,L-3-Cyanophenylalanine-Pregabalin, L-4-Cyanophenylalanine-Pregabalin,L-3,4-Difluorophenylalanine-Pregabalin,L-3,5-Difluorophenylalanine-Pregabalin, D,L-2,4-Difluorophenylalanine-Pregabalin, D,L-2,6-Difluorophenylalanine-Pregabalin,L-2,4-Dichlorophenylalanine-Pregabalin,L-3,4-Dichlorophenylalanine-Pregabalin, L-Pipecolyl-Pregabalin,L-tert-Butylglycine-Pregabalin, L-2,3-Diaminopropionyl-Pregabalin,L-Norvaline-Pregabalin, L-Penicillamine-Pregabalin,1-Aminocyclopropane-1-Carbonyl-Pregabalin,1-Aminocyclohexane-1-Carbonyl-Pregabalin,L-Homophenylalanine-Pregabalin, L-Aspartyl-β-(Pyrrolidinyl)-Pregabalin,L-Aspartyl-β-(Butylamido)-Pregabalin,L-Aspartyl-β-(2-Methoxyethylamido)-Pregabalin,L-Aspartyl-β-(Piperidinyl)-Pregabalin,L-Aspartyl-β-(3-Methylbutylamido)-Pregabalin,L-Aspartyl-β-(Cyclohexylamido)-Pregabalin,L-Aspartyl-β-(4-Amidomethylpyridine)-Pregabalin,L-Aspartyl-β-(3-Amidomethylpyridine)-Pregabalin,L-Aspartyl-β-(Heptylamido)-Pregabalin,L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Pregabalin,L-Aspartyl-β-(O-Cyclohexyl ester)-Pregabalin, L-Aspartyl-β-(O-Benzylester)-Pregabalin, L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Pregabalin,L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Pregabalin,L-Tyrosine-(O-2-Methylbenzoyl)-Pregabalin andL-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Pregabalin.
 25. A GABA analogderivative comprising a compound of Formula (Ia):H—I_(i)-J_(j)-D-K_(k)—OH   (Ia) wherein: H is hydrogen; I is—[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—; J is—[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—; K is—[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—; wherein a, b, c, d, e and fare independently 0 or 1, provided that at least one of a and b is 1, atleast one of c and d is 1, and at least one of e and f is 1; and whereini, j and k are independently 0 or 1, provided that at least one of i, jand k is 1; D is a moiety derived from a GABA analog having thefollowing structure:

wherein: R³ is a covalent bond linking the GABA analog moiety to J_(j);R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring; R⁵ and R⁶ are independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl,or R⁷ and R⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring; R⁹ is selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl,heteroaryl and substituted heteroaryl; R¹⁰ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl; R¹¹ isC(O)R¹², wherein R¹² is a covalent bond linking the moiety derived froma GABA analog to K_(k); R⁵⁰ is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁰ and R⁵¹ together with theatoms to which they are attached form a heterocyclyl ring; R⁵¹ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁵³ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵³ and R⁵⁴ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁵⁴ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵⁵ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵⁵ and R⁵⁶, together with the atoms to whichthey are attached form a heterocyclyl ring; R⁵⁶ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁵⁶ and R⁵⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R⁵⁶ and R⁵⁸ together with the atoms to which theyare attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R⁵⁷ is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶⁰ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁶⁰ and R⁶¹,together with the atoms to which they are attached form a heterocyclylring; R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶³ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶³ and R⁶⁴ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁶⁴ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; and pharmaceutically acceptable salts, hydrates and solvatesthereof, and provided that the compound of Formula (Ia) has a half-lifeof at least 1 hour when incubated in vitro at 37° C. at a concentrationof 5 μM with an S9 fraction of Caco-2 cell homogenate at a proteinconcentration of 0.5 mg/mL; and provided that if k is 0 then neither Inor J is derived from alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, valine or phenylglycine; and provided that whenR⁵, R⁶, R⁹ and R¹⁰ are each hydrogen, then R⁷ and R⁸ are neither bothhydrogen nor both methyl; and yet further provided that when D is eitherof the following moieties

neither I nor J are selected from the group of moieties consisting of:H₂NCH₂C(O)—, H₂NCH(CH₃)C(O)—, NH₂CH₂CH₂C(O)— and


26. A compound of claim 1, which upon oral administration of a dose ofGABA analog to a patient in need of therapy, provides therapeuticallyefficacious levels of a GABA analog in the plasma of the patient, wherethe GABA analog in the plasma of the patient has a concentration whichover time provides a curve of concentration of the GABA analog in theplasma over time, the curve having an area under the curve (AUC) whichis substantially more proportional to the dose of GABA analogadministered, as compared to the proportionality achieved following oraladministration of the GABA analog itself.
 27. A compound of claim 1,which upon oral administration of a dose of GABA analog to a patient inneed of therapy, provides therapeutically efficacious levels of a GABAanalog in the plasma of a patient, where the GABA analog in the plasmaof the patient has a concentration which over time provides a curve ofconcentration of the GABA analog in the plasma over time, the curvehaving a maximum plasma concentration (C_(max)) which is substantiallymore proportional to the dose of GABA analog administered, as comparedto the proportionality achieved following oral administration of theGABA analog itself.
 28. A compound of claim 1 which is metabolized toproduce a GABA analog at a sufficient rate in vivo, upon colonicadministration to rats, to produce a C_(max) of the GABA analog inplasma of at least 200% of the C_(max) of the GABA analog in plasmaachieved by colonically administering an equimolar dose of the GABAanalog itself.
 29. A compound of claim 1 which is metabolized to producea GABA analog at a sufficient rate in vivo, upon colonic administrationto rats, to produce a C_(max) of the GABA analog in plasma of at least1000% of the C_(max) of the GABA analog in plasma achieved bycolonically administering an equimolar dose of the GABA analog itself.30. A compound of claim 1 which is metabolized to produce a GABA analogat a sufficient rate in vivo, upon colonic administration to rats, toproduce an AUC of the GABA analog in plasma of at least 200% of the AUCof the GABA analog in plasma achieved by colonically administering anequimolar dose of the GABA analog itself.
 31. A compound of claim 1which is metabolized to produce a GABA analog at a sufficient rate invivo, upon colonic administration to rats, to produce an AUC of the GABAanalog in plasma of at least 500% of the AUC of the GABA analog inplasma achieved by colonically administering an equimolar dose of theGABA analog itself.
 32. A method for treating or preventing epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain, inflammatorydisease, insomnia, gastrointestinal disorders or ethanol withdrawalsyndrome in a patient, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a compoundaccording to claim
 1. 33. A method for treating or preventingneuropathic pain, muscular pain or skeletal pain in a patient,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound according to claim
 1. 34.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 35. A method for treating or preventing epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain, inflammatorydisease, insomnia, gastrointestinal disorders or ethanol withdrawalsyndrome in a patient, comprising administering to a patient in need ofsuch treatment a pharmaceutical composition according to claim
 34. 36. Amethod for treating or preventing neuropathic pain, muscular pain orskeletal pain in a patient, comprising administering to a patient inneed of such treatment a pharmaceutical composition according to claim34.
 37. An oral dosage form of a GABA analog derivative, comprising: asustained release oral dosage form containing a compound of claim 1, thedosage form being adapted for oral delivery to a patient; the dosageform further being adapted to release the compound gradually into theintestinal lumen of the patient over a period after oral administration.38. The dosage form of claim 37, wherein the period comprises at leastabout 6 hours.
 39. The dosage form of claim 37, wherein the periodcomprises at least about 8 hours.
 40. The dosage form of claim 37,wherein the period comprises at least about 12 hours.
 41. The dosageform of claim 37, wherein the dosage form releases from 0 to 20% of thecompound in 0 to 2 hours, from 20 to 50% of the compound in 2 to 12hours, from 50 to 85% of the compound in 3 to 20 hours and greater than75% of the compound in 5 to 18 hours.
 42. The dosage form of claim 37,wherein the dosage form comprises an osmotic dosage form.
 43. The dosageform of claim 37, wherein the dosage form comprises a compound-releasingpolymer.
 44. The dosage form of claim 37, wherein the dosage formcomprises a compound-releasing lipid.
 45. The dosage form of claim 37,wherein the dosage form comprises a compound-releasing wax.
 46. Thedosage form of claim 37, wherein the dosage form comprises tinytimed-release pills.
 47. The dosage form of claim 37, wherein the dosageform comprises compound-releasing beads.
 48. A method for achievingsustained release of a GABA analog in a patient in need of therapy,comprising orally administering to the patient a sustained releasedosage form containing a therapeutically effective amount of a compoundof claim
 1. 49. The method of claim 48, wherein the sustained releasedosage form further contains a pharmaceutically acceptable carrier. 50.A compound of claim 25, which upon oral administration of a dose of GABAanalog to a patient in need of therapy, provides therapeuticallyefficacious levels of a GABA analog in the plasma of the patient, wherethe GABA analog in the plasma of the patient has a concentration whichover time provides a curve of concentration of the GABA analog in theplasma over time, the curve having an area under the curve (AUC) whichis substantially more proportional to the dose of GABA analogadministered, as compared to the proportionality achieved following oraladministration of the GABA analog itself.
 51. A compound of claim 25,which upon oral administration of a dose of GABA analog to a patient inneed of therapy, provides therapeutically efficacious levels of a GABAanalog in the plasma of a patient, where the GABA analog in the plasmaof the patient has a concentration which over time provides a curve ofconcentration of the GABA analog in the plasma over time, the curvehaving a maximum plasma concentration (C_(max)) which is substantiallymore proportional to the dose of GABA analog administered, as comparedto the proportionality achieved following oral administration of theGABA analog itself.
 52. A compound of claim 25 which is metabolized toproduce a GABA analog at a sufficient rate in vivo, upon colonicadministration to rats, to produce a C_(max) of the GABA analog inplasma of at least 200% of the C_(max) of the GABA analog in plasmaachieved by colonically administering an equimolar dose of the GABAanalog itself.
 53. A compound of claim 25 which is metabolized toproduce a GABA analog at a sufficient rate in vivo, upon colonicadministration to rats, to produce a C_(max) of the GABA analog inplasma of at least 1000% of the C_(max) of the GABA analog in plasmaachieved by colonically administering an equimolar dose of the GABAanalog itself.
 54. A compound of claim 25 which is metabolized toproduce a GABA analog at a sufficient rate in vivo, upon colonicadministration to rats, to produce an AUC of the GABA analog in plasmaof at least 200% of the AUC of the GABA analog in plasma achieved bycolonically administering an equimolar dose of the GABA analog itself.55. A compound of claim 25 which is metabolized to produce a GABA analogat a sufficient rate in vivo, upon colonic administration to rats, toproduce an AUC of the GABA analog in plasma of at least 500% of the AUCof the GABA analog in plasma achieved by colonically administering anequimolar dose of the GABA analog itself.